Database: OMIM
Entry: 141900
LinkDB: 141900
MIM Entry: 141900
  The alpha and beta loci determine the structure of the 2 types of
  polypeptide chains in adult hemoglobin, Hb A. Mutant beta globin that
  sickles causes sickle cell anemia (603903). Absence of beta chain causes
  beta-zero-thalassemia. Reduced amounts of detectable beta globin causes
  beta-plus-thalassemia. For clinical purposes, beta-thalassemia is
  divided into thalassemia major (transfusion dependent), thalassemia
  intermedia (of intermediate severity), and thalassemia minor
  Patients with thalassemia major present in the first year of life with
  severe anemia; they are unable to maintain a hemoglobin level about 5
  gm/dl. Clinical details of this disorder have been detailed extensively
  in numerous monographs and are summarized by Weatherall et al. (1995).
  Modell et al. (2000) found that about 50% of U.K. patients with
  beta-thalassemia major die before the age of 35 years, mainly because
  conventional iron-chelation therapy is too burdensome for full
  To gain insight into the cellular and structural alterations of
  thalassemic bone, Mahachoklertwattana et al. (2003) studied bone
  histomorphometry and biochemical and hormonal profiles in children and
  adolescents with suboptimally treated beta-thalassemia disease.
  Seventeen patients underwent iliac crest bone biopsy for
  histomorphometric analyses. Most patients had growth retardation and
  delayed bone age. Bone mineral density (BMD) was low especially at the
  lumbar spine. Serum IGF1 (147440) levels were almost always low. Bone
  histomorphometry revealed increased osteoid thickness, osteoid
  maturation time, and mineralization lag time, which indicate impaired
  bone matrix maturation and defective mineralization. In addition, iron
  deposits appeared along mineralization fronts and osteoid surfaces. The
  authors concluded that delayed bone maturation and focal osteomalacia
  are the pathogenesis of bone disease in suboptimally blood-transfused
  thalassemics with iron overload. They suggested that iron deposits in
  bone and low circulating IGF1 levels may partly contribute to the above
  By autoradiography using heavy-labeled hemoglobin-specific messenger
  RNA, Price et al. (1972) found labeling of a chromosome 2 and a group B
  chromosome. They concluded, incorrectly as it turned out, that the
  beta-gamma-delta linkage group was on a group B chromosome since the
  zone of labeling was longer on that chromosome than on chromosome 2
  (which by this reasoning was presumed to carry the alpha locus or loci).
  Study of a case of the Wolf-Hirschhorn syndrome (4p-) suggested that the
  B group chromosome involved is chromosome 4. Barbosa et al. (1975)
  excluded recombination fraction of less than 0.30 for MN and Hb beta.
  Use of a combination of somatic cell hybridization and hybridization of
  DNA probes permitted assignment of the beta hemoglobin locus to
  chromosome 11 (Deisseroth et al., 1978). Parallel experiments showed
  that the gamma globin genes are also on chromosome 11, a result to be
  expected from other data indicating linkage of beta and gamma.
  Fine detail of both the mouse (Miller et al., 1978) and the human
  beta-globin gene was determined in the 1970s (Flavell et al., 1978). The
  mouse beta-globin gene is interrupted by 2 intervening sequences of DNA
  that divide it into 3 discontinuous segments. The entire gene, including
  the coding, intervening and untranslated regions, is transcribed into a
  colinear 15S mRNA precursor. Because mature globin mRNA is smaller (10S)
  and does not contain the intervening sequences, the 15S precursor must
  be processed. Using restriction endonucleases and recombinant DNA
  techniques, Flavell et al. (1978) prepared a map of the human beta- and
  delta-globin genes. The beta-globin gene contains a nonglobin DNA insert
  about 800-1000 basepairs in length, present within the sequence coding
  for amino acids 101-120. A similar untranscribed sequence may be present
  in the delta gene. They found that the distance between the beta and
  delta genes is about 7,000 nucleotide pairs and that the delta gene is
  to the 5-prime side of the beta gene, as predicted by other evidence.
  Polymorphism was found at the third nucleotide of the codon for amino
  acid number 50 (Wilson et al., 1977). Unlike the alpha locus which is
  double in most persons, the beta locus is unitary (unless the delta
  locus is considered the equivalent of the beta locus--a fully justified
  view). McCurdy et al. (1975) thought the beta locus in some persons
  might be duplicated; they observed a black woman who had hemoglobin A
  and 2 different variant hemoglobins, each with a beta-globin change. One
  of these, however, proved to be a posttranslational change (Charache et
  al., 1977). El-Hazmi et al. (1986) suggested that the presence of 2
  beta-globin genes might account for the finding of triple HpaI fragments
  in a case of sickle cell anemia. They explained its origin by unequal
  The order of the genes in the beta-globin cluster was proved by
  restriction enzyme studies (Fritsch et al., 1979); starting with the
  5-prime end, the order is gamma-G--gamma-A--delta--beta--Hpa I. By
  'liquid' molecular hybridization, Haigh et al. (1979) studied mouse-man
  hybrid rearrangements involving chromosome 11 and assigned the
  nonalpha-globin cluster to the region 11p11-p15. Housman et al. (1979)
  concluded from study of Chinese-hamster ovary cell lines containing
  chromosome 11 or selected parts thereof that the beta hemoglobin complex
  (NAG, nonalpha-globin genes) is in interband p1205-p1208. Housman et al.
  (1979) used a panel of hybrid hamster-human cells deleted by x-ray and
  selected by a double antibody technique (the method of Kao, Jones, and
  Puck) to assign the NAG cluster to 11p12, between LDHA distally and ACP2
  proximally. The orientation of the cluster in relation to the centromere
  was not known. Lebo et al. (1981) studied the linkage between 2
  restriction polymorphisms, the HpaI polymorphism on the 3-prime side of
  the beta-globin gene and the SacI polymorphism on the 5-prime side of
  the insulin gene. They found 4 recombinants in 34 meioses (12%), giving
  90% confidence limits for the interval as 6-22 cM. Given that the
  beta-globin gene is on 11p12 and the insulin gene on 11p15, that
  chromosome 11 represents about 4.8% of the genetic length of the genome,
  and that the total genetic length is 3,000 cM, then one would expect an
  interval of 29-42 cM.
  The beta-thalassemias were among the first human genetic diseases to be
  examined by means of new techniques of recombinant DNA analysis. In
  general, the molecular pathology of disorders resulting from mutations
  in the nonalpha-globin gene region is the best known, this elucidation
  having started with sickle cell anemia in the late 1940s. Steinberg and
  Adams (1982) reviewed the molecular defects identified in thalassemias:
  (1) gene deletion, e.g., of the terminal portion of the beta gene (Orkin
  et al., 1979); (2) chain termination (nonsense) mutations (Chang and
  Kan, 1979; Trecartin et al., 1981); (3) point mutation in an intervening
  sequence (Spritz et al., 1981; Westaway and Williamson, 1981); (4) point
  mutation at an intervening sequence splice junction (Baird et al.,
  1981); (5) frameshift deletion (Orkin and Goff, 1981); (6) fusion genes,
  e.g., the hemoglobins Lepore; and (7) single amino acid mutation leading
  to very unstable globin, e.g., Hb Vicksburg (beta 75 leu-to-0). Since it
  had been shown by cDNA-DNA hybridization that some cases of severe
  alpha-thalassemia result from deletion of all or most of the alpha
  globin genes, Ottolenghi et al. (1975) applied similar techniques to a
  study of whether beta genes were present in the forms of beta
  thalassemia with no synthesis of beta chains. They studied material from
  persons heterozygous for beta-zero-thalassemia and
  delta-beta-zero-thalassemia and concluded that at least one of the
  haploid genomes in this patient had a substantially intact beta globin
  gene. The beta globin structural gene is intact in beta-zero-thalassemia
  (Kan et al., 1975) but deleted in both hereditary persistence of fetal
  hemoglobin (Kan et al., 1975) and delta-zero-beta-zero-thalassemia
  (Ottolenghi et al., 1975). The possibility that the genetic lesions in
  beta-plus-thalassemia lie at splicing sites within intervening sequences
  of the beta globin gene was discussed by Maquat et al. (1980).
  Beta-zero-thalassemia is heterogeneous. Some cases have absent
  beta-globin mRNA. Some have a structurally abnormal beta-globin mRNA,
  usually in reduced amounts. Baird et al. (1981) found a nucleotide
  change at the splice junction at the 5-prime end of the large
  intervening sequence (IVS2) as the defect in 3 cases (1 Italian; 2
  Iranian). By means of a simplified method for trophoblast biopsy
  together with restriction endonuclease analysis of fetal DNA, Old et al.
  (1982) made first-trimester prenatal diagnosis in the case of 3 fetuses
  at risk for hemoglobinopathy: 2 at risk for homozygous beta-thalassemia
  and 1 at risk for sickle cell anemia.
  Conner et al. (1983) synthesized two 19-base-long oligonucleotides, 1
  complementary to the 5-prime end of the normal beta-globin gene and 1
  complementary to the sickle cell gene. DNA from normal homozygotes
  showed hybridization only for the first probe; DNA from persons with
  sickle cell anemia showed hybridization only with the second; DNA from
  sickle cell anemia heterozygotes showed hybridization with both.
  Allele-specific hybridization of oligonucleotides was proposed as a
  general method for diagnosis of any genetic disease which involves a
  point mutation in a single-copy gene. Saiki et al. (1985) developed a
  new method for rapid and sensitive diagnosis of sickle cell anemia that
  has potential use in connection with other genetic diseases. It combines
  2 methods: primer-mediated enzymatic amplification (about 220,000 times)
  of specific beta-globin target sequences in genomic DNA and restriction
  endonuclease digestion of an end-labeled oligonucleotide probe
  hybridized in solution to the amplified beta-globin sequences. In less
  than a day and with much less than a microgram of DNA, the diagnosis can
  be made. Saiki et al. (1988) devised a simple and rapid nonradioactive
  method for detecting genetic variation and applied it to the diagnosis
  of sickle cell anemia and beta-thalassemia. The procedure involved the
  selective amplification of a segment of the human beta-globin gene with
  oligonucleotide primers and a thermostable DNA polymerase, followed by
  hybridization of the amplified DNA with allele-specific oligonucleotide
  probes covalently labeled with horseradish peroxidase. The hybridized
  probes were detected with a simple colorimetric assay.
  In Sardinia, Rosatelli et al. (1985) used the synthetic oligonucleotide
  method for prenatal detection of the beta-zero-39 (nonsense) mutation
  type of beta-thalassemia. In a mouse model for beta-thalassemia, Holding
  and Monk (1989) were able to make the diagnosis in single blastomeres
  removed from embryos of 4 to 8 cells by PCR amplification. Monk and
  Holding (1990) demonstrated reproducible amplification of a 680-basepair
  sequence within the human beta-globin gene from individual human oocytes
  and the first polar bodies isolated from them. They used restriction
  enzyme digestion of the amplified DNA to confirm the identity of the
  fragment. The authors proposed that analysis of the DNA from the first
  polar body will facilitate preimplantation diagnosis of sickle cell
  anemia. Cai and Kan (1990) demonstrated the usefulness of denaturing
  gradient gel electrophoresis for detecting beta-thalassemia mutations
  and suggested that it might be a useful nonradioactive means of
  detecting mutations in other genetic disorders. Other methods are
  hybridization with allele-specific oligonucleotide probes, ribonuclease
  or chemical cleavage, and restriction endonuclease analysis. PCR greatly
  facilitated implementation of all these detection methods.
  In a family of Scottish-Irish descent, Pirastu et al. (1983) studied a
  new type of gamma-delta-beta thalassemia. The proposita presented with
  hemolytic disease of the newborn which was characterized by microcytic
  anemia. Initial restriction enzyme analysis showed no grossly abnormal
  pattern, but studies of polymorphic restriction sites and gene dosage
  showed extensive deletion of the entire beta-globin cluster. In situ
  hybridization with radioactive beta-globin gene probes showed that only
  one 11p homolog contained the beta-globin gene cluster. Kazazian et al.
  (1982) observed a similar extensive deletion in a Mexican family.
  From in situ hybridization studies, Morton et al. (1984) concluded that
  the beta-globin gene is situated at 11p15. Their studies included a
  t(7;11)(q22;p15) in which the beta-globin locus appeared to be at the
  junction point. Interest relates to the translocation cell line coming
  from a patient with erythroleukemia and the fact that the ERBB oncogene
  (131550) is located on chromosome 7 (7pter-q22).
  By analysis of family data on 15 restriction site polymorphisms (RSPs),
  Chakravarti et al. (1984) identified a 'hotspot' for meiotic
  recombination at the 5-prime end of the beta gene. Recombination
  leftward (in the 5-prime direction) from a point called chi near the end
  of the beta-globin gene is 3 to 30 times the expected rate; in the use
  of RSPs in prenatal diagnosis, it had been assumed that a marker 10 kb
  from a mutant gene would recombine at a rate of 10(-5) per kb, leading
  to a diagnostic error of 1 in 10,000. However, their data suggested the
  error rate using 'loci' on opposite sides of chi may be as high as 1 in
  312. By a computer search of the DNA sequences of the beta cluster, they
  located a chi sequence (5-prime-GCTGGTGG-3-prime) at the 5-prime end of
  the second intervening sequence of the beta gene. This chi sequence, a
  promoter of generalized recombination in lambda phage, has been found in
  high frequency in the mouse genome, especially in immunoglobulin DNA. A
  recombinational hotspot has been found in the mouse major
  histocompatibility complex. Matsuno et al. (1992) invoked possible gene
  conversion at the chi sequence near the 5-prime end of exon 2 (codons
  31-34) as the explanation for the finding of a beta-thalassemia mutation
  common in southeast Asia (frameshift mutation in codons 41 and 42; see
  141900.0326), as well as in Japan, on 2 different restriction frameworks
  (haplotypes). They presumed that the 6 families found in Japan with this
  particular mutation had inherited it from ancestors who had migrated to
  Japan from southeast Asia. In a large Amish pedigree, Gerhard et al.
  (1984) observed an apparent crossover within the beta-globin gene
  cluster in the region of the recombinational 'hotspot' postulated by
  Chakravarti et al. (1984) on the basis of linkage disequilibrium in
  population data. It was also possible to identify the orientation of the
  beta-globin cluster vis-a-vis the centromere:
  cen--5-prime--epsilon--beta--3-prime--pter. Camaschella et al. (1988)
  identified recombination between 2 paternal chromosomes in a region
  5-prime to the beta gene, previously indicated to contain a 'hotspot'
  for recombination. The recombination was identified because in the
  course of prenatal diagnosis by linkage to RFLPs, a homozygous
  beta-thalassemia fetus was misdiagnosed as beta-thalassemia trait. In
  the course of studying an Irish family with beta-thalassemia due to the
  Q39X mutation, Hall et al. (1993) found a fourth case of recombination
  in the beta-globin gene cluster. The event had occurred 5-prime of the
  polymorphic RsaI site at position -550 bp upstream of the beta-globin
  gene mRNA cap site, within the 9.1-kb region shown to be a hotspot for
  By high-resolution chromosome sorting of human chromosomes carrying
  segments of chromosome 11 and by spot blotting with various
  gene-specific probes, Lebo et al. (1985) concluded that the loci for
  parathyroid hormone, beta-globin, and insulin are all located on 11p15.
  By in situ hybridization studies of chromosome 11 rearrangements,
  Magenis et al. (1985) likewise assigned HBB to 11p15. In an addendum,
  they referred to studies of a t(7;11) rearrangement that further
  narrowed the HBB assignment to 11p15.4-11pter. Although some workers
  have put the insulin (176730), beta-globin, and HRAS (190020) genes on
  11p15, Chaganti et al. (1985) located these differently by in situ
  hybridization to meiotic chromosomes: INS, 11p14.1; HRAS, 11p14.1; HBB,
  11p11.22; and PTH (not previously assigned), 11p11.21. By
  high-resolution cytogenetics and in situ hybridization, Lin et al.
  (1985) placed the beta-globin gene in the 11p15.4-p15.5 segment. Through
  reanalysis of a Chinese hamster/human cell hybrid that had lost all
  human chromosomes except 11, Gerhard et al. (1987) reached the
  conclusion that the beta-globin gene complex is located in 11p15 and
  that the insulin and HRAS1 genes are located in a segment of DNA
  approximately 10 megabases long.
  Huang et al. (1986) reported the same 'TATA' box mutation leading to the
  same nondeletion form of beta-thalassemia in Chinese as had been
  reported in American blacks by Antonarakis et al. (1984); see
  141900.0379. There are other illustrations indicating that mutations in
  the beta-globin gene can recur.
  Part of the mutational repertoire of the beta-globin locus is hereditary
  persistence of fetal hemoglobin (HPFH) due to deletion. Two types (types
  I and II) occur in blacks and have as their basis deletion of the delta
  and beta loci. An Italian type and an Indian type are likewise deletion
  forms of HPFH; see review by Saglio et al. (1986). In 2 Italian brothers
  with a G-gamma/A-gamma form of hereditary persistence of fetal
  hemoglobin, Camaschella et al. (1990) demonstrated a deletion starting
  3.2 kb upstream from the delta gene and ending within the enhancer
  region 3-prime to the beta-globin gene. The deletion removed 1 of the 4
  binding sites for an erythroid specific transcriptional factor (NF-E1).
  It appeared that the residual enhancer element, relocated near gamma
  genes, may increase fetal hemoglobin expression.
  Orkin et al. (1982) developed and applied a new strategy for the
  comprehensive analysis of existing mutations in a class of human
  disease. They combined analysis of various restriction enzyme
  polymorphisms in the beta-globin gene cluster with direct examination of
  beta-globin structural genes in Mediterranean persons with
  beta-thalassemia. The approach was prompted by the finding that specific
  mutant genes are strongly linked to patterns of restriction site
  polymorphism (haplotypes) in this region of the genome. They isolated 8
  different mutant genes among the 9 different haplotypes represented in
  Mediterraneans. Seven of the 8 genes were present in Italians from
  various locales in Italy, and 6 in Greeks. Several were previously
  unknown mutations, and 1 of these possibly affects transcription. The
  strategy is probably applicable to the analysis of heterogeneity in
  other diseases of single-copy genes. When linkage analysis can be
  performed in the family, the haplotype analysis will be highly useful in
  prenatal diagnosis of beta-thalassemia. Indeed, the method of
  haplotyping proved highly useful both in tracing the origin of mutations
  and in family studies (see Antonarakis et al., 1982). Losekoot et al.
  (1992) described a method for rapid detection of beta-globin haplotypes
  (referred to by them as framework) by denaturing gradient gel
  Rosatelli et al. (1987) analyzed the molecular defect in 494 Sardinian
  beta-thalassemia heterozygotes. The most prevalent mutation, accounting
  for 95.4% of cases, was the nonsense mutation at codon 39. The
  remainder, in decreasing order of frequency, were a frameshift at codon
  6 (2.2%), beta-plus IVS1, nucleotide 110 (0.4%), and beta-plus IVS2,
  nucleotide 745 (0.4%). The DNA sequences along the human beta-globin
  cluster are highly polymorphic; over 20 polymorphic restriction
  endonuclease sites have been described in this 60-kb region. As outlined
  earlier, with examples, RFLP haplotypes have been useful in defining
  various thalassemia lesions, such as deletions, for prenatal diagnosis
  of beta-thalassemia, and for tracing the origin and migration of mutant
  genes. Pirastu et al. (1987) found that the predominant beta-thalassemia
  in Sardinia, the beta-zero type due to nonsense mutation (CAG-to-TAG) at
  beta-39, resides on 9 different chromosome haplotypes. One of the
  haplotypes included a cytosine-to-thymine point mutation 196 nucleotides
  upstream from the A-gamma-globin gene (142200). This mutation at
  position -196 is associated with high levels of production of fetal
  hemoglobin. The beta-39 nonsense mutation may have gotten onto the -196
  chromosome through crossing-over. A chromosome carrying such a double
  mutation could be expected to impart selective advantage because the
  beta-thalassemia would protect against malaria while the increased
  gamma-globin production would ameliorate the severity of the
  beta-thalassemia. A similar mechanism may have been operative in the
  case of another haplotype which combined the beta-39 nonsense mutation
  with triple gamma loci produced by the addition of a second
  G-gamma-globin gene. Pirastu et al. (1987) proposed a schema by which
  the findings were explained by a single initial mutation with subsequent
  crossovers between the 5-prime and 3-prime blocks of genes producing 6
  other chromosomes and then the creation of 2 others by crossing-over and
  gene conversion. Additional diversity could have arisen through other
  beta-39 mutations. The mutation identified in a family of northern
  European origin by Chehab et al. (1986) was of this type.
  Wainscoat et al. (1983) showed that coinheritance of alpha-thalassemia
  with homozygous beta-thalassemia resulted in amelioration of the
  beta-thalassemia. Kulozik et al. (1987) showed that heterozygous
  beta-thalassemia was associated with unusually severe clinical
  manifestations when coinherited with an extra alpha-globin gene; in each
  of 5 cases 1 chromosome 16 carried 3 alpha-globin genes. Camaschella et
  al. (1987) found the same aggravation of the clinical picture with
  triplicated alpha locus. This is a particularly instructive example of
  gene interaction. Direct sequencing of specific regions of genomic DNA
  became feasible with the invention of PCR, which permits amplification
  of specific regions of DNA (Church and Gilbert, 1984; Saiki et al.,
  1986). For example, Wong et al. (1986) amplified human mitochondrial DNA
  and sequenced it directly. Wong et al. (1987) applied a combination of
  PCR and direct sequence analysis of the amplified product to the study
  of beta-thalassemia in 5 patients whose mutant alleles had not been
  characterized. They found 2 previously undescribed mutations along with
  3 previously known ones. One new allele was a frameshift at codons
  106-107 and the other was an A-to-C transversion at the cap site (+1) of
  the beta-globin gene. The latter was the first natural mutation observed
  at the cap site (141900.0387).
  In the so-called Corfu form of delta-beta-zero-thalassemia, Kulozik et
  al. (1988) found that a deletion removed 7,201 basepairs containing part
  of the delta-globin gene and sequences upstream. The beta-globin gene
  contained a G-to-A mutation at position 5 in IVS1. The gamma-globin gene
  promoters were normal. In transfected HeLa cells, a normal message was
  produced from the mutated beta-globin gene at a level of approximately
  20% of the normal, the remaining 80% being spliced at cryptic sites in
  exon 1 and intron 1. This indicated that the mutation in the beta-globin
  gene is not the sole cause of the complete absence of hemoglobin A in
  this form of thalassemia. Kulozik et al. (1988) concluded that the
  7.2-kb deletion contains sequences necessary for the normal activation
  of the beta-globin gene. In the homozygous state there is complete
  absence of hemoglobin A and hemoglobin A(2) and a high level of
  hemoglobin F. Traeger-Synodinos et al. (1991) gave further data on the
  Corfu mutation. In a study of beta-thalassemia in Spain, Amselem et al.
  (1988) demonstrated the usefulness of the dot-blot hybridization of
  PCR-amplified genomic DNA in both rapid population surveys and prenatal
  diagnosis. They found 7 different beta-thalassemia mutations. The
  nonsense codon 39 accounted for 64%, whereas the IVS1 position 110
  mutation (141900.0364), the most common cause of beta-thalassemia in the
  eastern part of the Mediterranean basin, was underrepresented (8.5%).
  The IVS1 mutation at position 6 (141900.0360) accounted for 15% of the
  defects and led to a more severe form of beta(+)-thalassemia than
  originally described in most patients with this mutation. Diaz-Chico et
  al. (1988) described 2 families, 1 Yugoslavian and 1 Canadian, with
  heterozygous thalassemia characterized by mild anemia with severe
  microcytosis and hypochromia, normal levels of hemoglobin A(2), and
  slightly raised hemoglobin F levels. In both families the condition
  resulted from large deletions which included all functional and
  pseudogenes of the beta-globin gene cluster. The deletion was at least
  148 kb in the Yugoslavian family and 185 kb in the Canadian family.
  Kazazian and Boehm (1988) gave an update on the variety of
  beta-thalassemias. Large deletions are a rare cause of beta-thalassemia;
  as of early 1989, 63 single nucleotide substitutions or small deletions
  and 7 large deletions had been described as the basis of
  beta-thalassemia (Kazazian, 1989). Aulehla-Scholz et al. (1989)
  described a deletion comprising about 300 basepairs in a female
  heterozygote, resulting in loss of exon 1, part of IVS1, and the 5-prime
  beta-globin gene promoter region. Laig et al. (1989) identified new
  beta-thalassemia mutations in northern and northeastern Thailand. Rund
  et al. (1991) studied beta-thalassemia among the Kurdistan Jews. They
  identified 13 distinct mutations among 42 sibships, of which 3 were
  previously undescribed. Four of the mutations (see 141900.0331,
  141900.0341, 141900.0373, 141900.0383) were unique to Kurdish Jews and
  two-thirds of the mutant chromosomes carried the mutations unique to
  Kurdish Jews. Haplotype and geographic analyses suggested that
  thalassemia in central Kurdistan has evolved from multiple mutational
  events. Genetic admixture with the local population appears to be the
  primary mechanism of the evolution of thalassemia in Turkish Kurdistan,
  whereas there is evidence for a founder effect in Iranian Kurdistan.
  Huang et al. (1990) used DNA from dried blood specimens amplified by PCR
  to study the distribution of beta-thalassemia mutations in southern,
  western, and eastern China. Huisman (1990) provided a list of over 110
  different beta-thalassemia alleles, most of them of the nondeletional
  As indicated by the work of Villegas et al. (1992), Oron et al. (1994),
  and Traeger-Synodinos et al. (1996), the thalassemia intermedia is
  caused by interaction between a triplicated alpha-globin locus (leading
  to alpha-globin overproduction) and beta-thalassemia heterozygosity.
  Traeger-Synodinos et al. (1996) reported 3 cases of beta-thalassemia
  heterozygosity with homozygous alpha-globin gene triplication and 17
  beta-thalassemia heterozygotes with a single additional alpha-globin
  gene. Garewal et al. (1994) likewise reported 2 patients with a clinical
  presentation of thalassemia intermedia due to homozygosity for
  alpha-gene triplication and heterozygosity for an HBB gene mutation.
  Huisman (1992) edited an up-to-date listing of the deletions, mutations,
  and frameshifts leading to beta-thalassemia, which had been published 3
  times previously, and added a new table on the delta-thalassemias,
  prepared by Erol Baysal. Kazazian et al. (1992) tabulated a total of 9
  beta-globin mutations producing dominant thalassemia-like phenotypes.
  Widespread ethnic derivation was demonstrated.
  Krawczak et al. (1992) reviewed the mutational spectrum of single
  basepair substitutions in mRNA splice junctions on the basis of 101
  different examples of point mutations occurring in the vicinity of
  splice junctions and held to be responsible for human genetic disease.
  The data comprised 62 mutations at 5-prime splice sites, 26 at 3-prime
  splice sites, and 13 that resulted in the creation of novel splice sites
  such as Hb E. They estimated that up to 15% of all point mutations
  causing human genetic disease result in an mRNA splicing defect.
  Carver and Kutlar (1995) listed 323 beta-chain variants as of January
  1995. This number did not include beta-chain variants with deletions
  and/or insertions or those with extended polypeptide chains. Baysal and
  Carver (1995) provided an update (eighth edition) of their catalog, or
  repository, of beta-thalassemia and delta-thalassemia.
  Landin et al. (1996) noted that 34 of 316 beta-globin variants due to
  single amino acid substitutions could be caused by more than 1 type of
  point mutation at the DNA level. They also noted that 3 beta-globin
  variants (Hb Edmonton, Hb Bristol, and Hb Beckman) and 1 alpha-globin
  variant (Hb J-Kurosh) could not be produced by a single nucleotide
  substitution; 2 substitutions were required.
  Huisman et al. (1996) provided a syllabus of human hemoglobin variants
  listing the characteristics as well as precise molecular change of known
  beta-globin mutants; these numbered 335 single-base mutations and 17
  variants with 2 amino acid replacements as of January 1996. They also
  included hemoglobin variants resulting from fusion of parts of the
  beta-chain and delta-chain, variants with elongated beta-chains at both
  the C-terminal and N-terminal ends, and variants with small deletions
  and/or insertions in the beta-chain. Not included were deletions and
  mutations that result in beta-thalassemia, even if such a change, point
  mutation, or frameshift occurred in one of the coding regions of the HBB
  gene. Information regarding these abnormalities were provided elsewhere,
  e.g., Baysal and Carver (1995). Huisman et al. (1996) stated that 138 of
  the 146 codons of the HBB gene have been mutated; 5 mutations are known
  for 6 codons (22, 67, 97, 121, 143, and 146), 6 mutations for codon 92,
  and 7 mutations for codon 99. Most of the mutations have been deduced
  from the sequence of the amino acid sequence of the variant protein and
  the known sequence of the HBB gene; slightly more than 10% of the
  mutations have been determined through DNA sequencing. Occasionally
  discrepancy was observed, such as at position 50 and 67 of the
  beta-globin chain. (Some authors, Boyer et al. (1972), Charache et al.
  (1975), and Brennan et al. (1982), use polycythemia rather than
  erythrocytosis as the designation for the compensatory increase in red
  blood cell mass that accompanies hemoglobins with increased oxygen
  affinity. The 2 terms must be considered synonymous. Some, e.g.,
  Hamilton et al. (1969), use erythemia. Although also a synonym of
  polycythemia and erythrocytosis, erythemia has become essentially
  Huisman et al. (1996) listed (in their Table 6B) 38 HBB variants causing
  erythrocytosis, plus 20 others causing mild erythrocytosis and 1 causing
  erythrocytosis in combination with hemolysis.
  Sierakowska et al. (1996) found that treatment of mammalian cells stably
  expressing the IVS2-654 beta HBB gene (141900.0348) with antisense
  oligonucleotides targeted at the aberrant splice sites restored correct
  splicing in a dose-dependent fashion, generating correct human
  beta-globin mRNA and polypeptide. Both products persisted for up to 72
  hours after treatment. The oligonucleotides modified splicing by a true
  antisense mechanism without overt unspecific effects on cells growth and
  splicing of other pre-mRNAs. This novel approach in which antisense
  oligonucleotides are used to restore rather than to downregulate the
  activity of the target gene is applicable to other splicing mutants and
  is of potential clinical interest.
  Several hemoglobin variants were first detected in the course of study
  of glycated hemoglobin (Hb A1c) in diabetics, e.g., 141900.0429 and
  141900.0477. The alternative situation, diagnosis of diabetes during the
  performance of hemoglobin electrophoresis for study of anemia, was
  observed by Millar et al. (2002).
  Hardison et al. (2002) constructed a web-accessible relational database
  of hemoglobin variants and thalassemia mutations called HbVar, in which
  old and new data are incorporated. Queries can be formulated based on
  fields in the database. For example, tables of common categories of
  variants, such as all variants involving the HBA1 gene (141800) or all
  those that result in high oxygen affinity, can be assembled. More
  precise queries are possible, such as 'all beta-globin variants
  associated with instability and found in Scottish populations.'
  In Lebanon, beta-thalassemia is the predominant genetic defect. Makhoul
  et al. (2005) investigated the religious and geographic distribution of
  beta-thalassemia mutations in Lebanon and traced their origins. Sunni
  Muslims had the highest beta-thalassemia carrier rate and presented the
  greatest heterogeneity, with 16 different mutations. Shiite Muslims
  followed closely with 13 mutations, whereas Maronites represented 11.9%
  of all beta-thalassemic subjects and carried 7 different mutations. RFLP
  haplotype analysis showed that the observed genetic diversity originated
  from both new mutational events and gene flow from population migration.
  Ding et al. (2004) described a method for noninvasive prenatal diagnosis
  by analysis of circulating nucleic acids. Circulating fetal-specific DNA
  sequences have been detected and constitute a fraction of the total DNA
  in maternal plasma. The robust discrimination of single-nucleotide
  differences between circulating DNA species is technically challenging
  and demanded the adoption of highly sensitive and specific analytical
  systems. Ding et al. (2004) developed a method based on single-allele
  base extension reaction and mass spectrometry which allowed for the
  reliable detection of fetal-specific alleles, including point mutations
  and SNPs, in maternal plasma. The approach was applied to exclude the
  fetal inheritance of the 4 most common Southeast Asian beta-thalassemia
  mutations in at-risk pregnancies between weeks 7 and 21 of gestation:
  41/42delCTTT (141900.0326), IVS2 654C-T (141900.0368), -28A-G
  (141900.0381), and 17A-T (141900.0311). Fetal genotypes were correctly
  predicted in all cases studied. Fetal haplotype analysis based on a SNP
  linked to the HBB gene in maternal plasma also was achieved.
  Dye and Proudfoot (2001) performed in vivo analysis of transcriptional
  termination for the human beta-globin gene and demonstrated
  cotranscriptional cleavage (CoTC). This primary cleavage event within
  beta-globin pre-mRNA, downstream of the poly(A) site, is critical for
  efficient transcriptional termination by RNA polymerase II (see 180660).
  Teixeira et al. (2004) showed that the CoTC process in the human
  beta-globin gene involves an RNA self-cleaving activity. They
  characterized the autocatalytic core of the CoTC ribozyme and showed its
  functional role in efficient termination in vivo. The identified core
  CoTC is highly conserved in the 3-prime flanking regions of other
  primate beta-globin genes. Functionally, it resembles the 3-prime
  processive, self-cleaving ribozymes described for the protein-encoding
  genes from the myxomycetes Didymium iridis and Physarum polycephalum,
  indicating evolutionary conservation of this molecular process. Teixeira
  et al. (2004) predicted that regulated autocatalytic cleavage elements
  within pre-mRNAs may be a general phenomenon and that functionally it
  may provide an entry point for exonucleases involved in mRNA maturation,
  turnover, and, in particular, transcriptional termination.
  It is increasingly appreciated that the spatial organization of DNA in
  the cell nucleus is a key contributor to genomic function. Simonis et
  al. (2006) developed 4C technology (chromosome conformation capture
  (3C)-on-chip), which allowed for an unbiased genomewide search for DNA
  loci that contact a given locus in the nuclear space. They demonstrated
  that active and inactive genes are engaged in many long-range
  interchromosomal interactions and can also form interchromosomal
  contacts. The active beta-globin locus in the mouse fetal liver
  preferentially contacts transcribed, but not necessarily
  tissue-specific, loci elsewhere on chromosome 7, whereas the inactive
  locus in fetal brain contacts different transcriptionally silent loci. A
  housekeeping gene in a gene-dense region on chromosome 8 of the mouse,
  Rad23a (600061), formed long-range contacts predominantly with other
  active gene clusters, both in cis and in trans, and many of these intra-
  and interchromosomal interactions were conserved between the tissues
  analyzed. The data demonstrated that chromosomes fold into areas of
  active chromatin and areas of inactive chromatin and established 4C
  technology as a powerful tool to study nuclear architecture.
  Uda et al. (2008) found that the C allele of dbSNP rs11886868 in the
  BCL11A gene (606557.0002) was associated with an ameliorated phenotype
  in patients with beta-thalassemia due to increased production of fetal
  Schoenfelder et al. (2010) found that mouse Hbb and Hba associated with
  hundreds of active genes from nearly all chromosomes in nuclear foci
  that they called 'transcription factories.' The 2 globin genes
  preferentially associated with a specific and partially overlapping
  subset of active genes. Schoenfelder et al. (2010) also noted that
  expression of the Hbb locus is dependent upon Klf1 (600599), while
  expression of the Hba locus is only partially dependent on Klf1.
  Immunofluorescence analysis of mouse erythroid cells showed that most
  Klf1 localized to the cytoplasm and nuclear Klf1 was present in discrete
  sites that overlapped with RNAII foci. Klf1 knockout in mouse erythroid
  cells specifically disrupted the association of Klf1-regulated genes
  within the Hbb-associated network. Klf1 knockout more weakly disrupted
  interactions within the specific Hba network. Schoenfelder et al. (2010)
  concluded that transcriptional regulation involves a complex
  3-dimensional network rather than factors acting on single genes in
  Gouagna et al. (2010) used cross-sectional surveys of 3,739 human
  subjects and transmission experiments involving 60 children and over
  6,000 mosquitoes in Burkina Faso, West Africa, to test whether the HBB
  variants HbC (141900.0038) and HbS (141900.0243), which are protective
  against malaria, are associated with transmission of the parasite from
  the human host to the Anopheles mosquito vector. They found that HbC and
  HbS were associated with significant 2-fold in vivo (P = 1.0 x 10(-6))
  and 4-fold ex vivo (P = 7.0 x 10(-5)) increases of parasite transmission
  from host to vector. Gouagna et al. (2010) concluded that human genetic
  variation at the HBB locus can influence the efficiency of malaria
  transmission, possibly by promoting sexual differentiation of P.
  falciparum as a downstream phenotypic event. Alternatively, Gouagna et
  al. (2010) suggested that the higher infectivity of individuals with HBB
  variants in their study could be due to less frequent use of
  antimalarial drugs. In a commentary, Pasvol (2010) noted that little is
  known regarding the mechanisms involved in switching from the parasite
  asexual stages to the induction of gametogenesis, but that the
  hemoglobinopathies may provide a scenario beneficial to both host and
  - Locus Control Region Beta
  Cases of gamma-delta-beta thalassemia are known in which the beta gene
  is intact but deletion 'in cis' occurs upstream, even at a distance, in
  a region designated LCRB. In a remarkable case reported by Curtin et al.
  (1985), a deletion extended from the third exon of the G-gamma gene
  upstream for about 100 kb. The A-gamma, pseudo-beta, delta, and beta
  genes in cis were intact. This malfunction of the beta-globin gene on a
  chromosome in which the deletion is located 25 kb away suggests that
  chromatin structure and conformation are important for globin gene
  expression. In experiments in which the human beta-globin locus was
  introduced into the mouse genome, Talbot et al. (1989) found a 6.5-kb
  control region which allowed achievement of endogenous levels of
  beta-globin expression. The control region included an erythroid
  cell-specific DNase I hypersensitive site (HS). Using pulsed field gel
  electrophoresis and PCR, Driscoll et al. (1989) found, in a case of
  gamma-delta-beta-thalassemia, a de novo deletion on a maternally
  inherited chromosome 11 involving about 30 kb of sequences 5-prime to
  the epsilon gene. The deletion extended from -9.5 kb to -39 kb 5-prime
  of epsilon and included 3 of the 4 DNase I hypersensitive sites (at
  -10.9 kb, -14.7 kb, and -18 kb 5-prime of epsilon). The remaining
  sequences of the beta-globin complex, including the DNase I
  hypersensitive sites at -6.1 kb and all structural genes in cis to the
  deletion, were physically intact. Again, a significance of the
  hypersensitive sites in regulating globin-gene expression was
  Epsilon-gamma-delta-beta-thalassemias are all caused by deletions of the
  beta-globin gene cluster on 11p. At the molecular level, the deletions
  fall into 2 categories: group I removes all or a greater part of the
  beta-globin cluster, including the beta-globin gene; group II removes
  extensive upstream regions leaving the beta-globin gene itself intact
  despite which its expression is silenced because of inactivation of the
  upstream beta-locus control region. A group I deletion was reported by
  Curtin et al. (1985). A group I deletion was reported in a Chilean
  family by Game et al. (2003), and an upstream deletion (group II) was
  reported in a Dutch family by Harteveld et al. (2003). Rooks et al.
  (2005) described 3 novel epsilon-gamma-delta-beta-thalassemia deletions
  in 3 English families, referred to as English II, III, and IV to
  distinguish them from the family of Curtin et al. (1985), which was also
  English (I). Two of the deletions removed the entire beta-globin gene
  complex, including a variable number of flanking olfactory receptor
  The significance of the hypersensitive sites to globin gene expression
  had also been demonstrated by Grosveld et al. (1987) who achieved high
  levels of position-independent beta-gene expression in transgenic mice
  with a specially constructed beta-globin minilocus in which 5-prime and
  3-prime hypersensitive sequences flanked a beta-globin gene. The
  hypersensitive sequences, termed locus-activating regions (LARs), are
  erythroid-tissue-specific and developmentally stable. Curtin et al.
  (1989) performed experiments similar to those of Grosveld et al. (1987)
  with like results. (A similar positive control region for the cluster of
  alpha-globin genes was deduced by Hatton et al. (1990) on the basis of
  deletion in a case of alpha-thalassemia; see 141800.) See 187550 for
  evidence of an unlinked remote regulator of HBB gene expression. Townes
  and Behringer (1990) reviewed the topic of the locus activating region.
  They presented a model for developmental control of human globin gene
  expression (see their Figure 2). With respect to the cap site of the
  human epsilon-globin gene, LAR site I is located at position -6.1 kb;
  site II, at -10.9 kb; site III, at -14.7 kb; and site IV, at -18 kb.
  Moon and Ley (1990) cloned murine DNA sequences homologous to the human
  LAR site II. These sequences are linked to the mouse beta-globin gene
  cluster in the same basic arrangement as the human beta-globin gene
  cluster. Furthermore, the 2 LARs share 70% identical sequence and
  several enhancer-type functions. LAR sequences are almost certainly not
  confined to the human beta-globin locus. The investigators stated that
  these sequences may be critical components of any gene family that
  comprises multiple members that are regulated differently during
  Perichon et al. (1993) demonstrated interethnic polymorphism of 1
  segment of the LCRB region in sickle cell anemia patients. Distinct
  polymorphic patterns of a simple sequence repeat were observed in strong
  linkage disequilibrium with each of the 5 major beta-S haplotypes.
  Studies by Grosveld et al. (1987) and by Blom van Assendelft et al.
  (1989) established that 6 DNase I hypersensitive sites flank the globin
  genes. One HS site is located 20 kb downstream of the beta-globin
  cluster and 5 HS sites are located 6-22 kb upstream within the locus
  control region (LCR). Peterson et al. (1996) examined the effects of
  deletion of the LCR 5-prime HS3 element and the 5-prime HS2 element on
  globin gene expression by recombining a 2.3-kb deletion of 5-prime HS3
  or a 1.9-kb deletion of 5-prime HS2 into a beta-globin locus YAC, which
  was then used to produce transgenic mice. When the LCR 5-prime HS3
  element is deleted there is decreased expression of epsilon-globin in
  the yolk sac. Deletion of 5-prime HS2 resulted in a minor but
  statistically significant decrease in epsilon-, gamma-, and beta-globin
  expression. From these results Peterson et al. (1996) concluded that
  there is functional redundancy among the HS sites. The effects of the
  5-prime HS3 deletion on epsilon-globin gene expression led them to
  conclude that specific interactions between the HSs and the globin genes
  underlie activation of globin genes during specific stages of
  Epner et al. (1998) deleted the murine beta-globin LCR from its native
  chromosomal location. The approximately 25-kb deletion eliminated all
  sequences and structures homologous to those defined as the human LCR.
  In differentiated embryonic stem cells and erythroleukemia cells
  containing the LCR-deleted chromosome, DNase I sensitivity of the
  beta-globin domain was established and maintained, developmental
  regulation of the locus was intact, and beta-like globin RNA levels were
  reduced 5 to 25% of normal. Thus, in the native murine beta-globin
  locus, the LCR was necessary for normal levels of transcription, but
  other elements were sufficient to establish the open chromatin
  structure, transcription, and developmental specificity of the locus.
  These findings suggest a contributory rather than dominant function for
  the LCR in its native location.
  Bauchwitz and Costantini (2000) quantified the effects of beta-globin
  sequence modifications on epsilon-, gamma-, and delta-globin levels in
  transgenic mice. Embryonic day 11.5 primitive erythroid cells showed a
  large increase in epsilon-globin in the absence of the beta-globin gene,
  which is weakly expressed at that stage of development. Embryonic day
  17.5 fetal liver and adult erythroid cells, in which beta-globin
  expression approaches its maximum, showed only a small stimulation of
  gamma- and delta-globin levels in the absence of beta-globin sequence.
  Analysis of erythroid colonies produced by in vitro differentiation of
  embryonic stem cells indicated that the absence of the human beta-globin
  gene had no effect on gamma-globin expression. The authors concluded
  that competitive influences need not be linked directly to
  transcriptional level or distance from the LCR, and that the large
  increases in gamma-globin levels seen in some human deletional
  beta-thalassemias and hereditary persistence of fetal hemoglobin
  conditions are most likely due to effects other than loss of beta-globin
  competition. In transgenic mice with beta-globin sequences inserted
  between epsilon and the LCR in a beta-locus, the expression of epsilon-,
  gamma-, and delta-globins suggested that stage-specific sensitivity to
  loss of LCR activity may be a more important parameter than position
  relative to the LCR.
  Alami et al. (2000) created a yeast artificial chromosome containing an
  unmodified human beta-globin locus, and introduced it into transgenic
  mice at various locations in the genome. The locus was not subject to
  detectable stable position effects but did undergo mild-to-severe
  variegating position effects at 3 of the 4 noncentromeric integration
  sites tested. The distance and the orientation of the LCR relative to
  the regulated gene contributed to the likelihood of variegating position
  effects, and affected the magnitude of its transcriptional enhancement.
  DNaseI hypersensitive site (HSS) formation varied with the proportion of
  expressing cells (variegation), rather than the level of gene
  expression, suggesting that silencing of the transgene may be associated
  with a lack of HSS formation in the LCR region. The authors concluded
  that transcriptional enhancement and variegating position effects are
  caused by fundamentally different but interdependent mechanisms.
  Navas et al. (2002) generated transgenic mouse lines carrying a
  beta-globin locus YAC lacking the LCR to determine if the LCR is
  required for globin gene activation. Beta-globin gene expression was
  analyzed by RNase protection, but no detectable levels of epsilon-,
  gamma-, and beta-globin gene transcripts were produced at any stage of
  development. Lack of gamma-globin gene expression was also seen in a
  beta-YAC transgenic mouse carrying a gamma-globin promoter mutant that
  causes hereditary persistence of fetal hemoglobin (see 142200.0026) and
  an HS3 core deletion that specifically abolishes gamma-globin gene
  expression during definitive erythropoiesis. The authors concluded that
  the presence of the LCR is a minimum requirement for globin gene
  Navas et al. (2003) assessed the contribution of the GT6 motif within
  HS3 of the LCR on downstream globin gene expression by mutating GT6 in a
  beta-globin locus YAC and measuring the activity of beta-globin genes in
  GT6-mutated beta-YAC transgenic mice. They found reduced expression of
  epsilon- and gamma-globin genes during embryonic erythropoiesis. During
  definitive erythropoiesis, gamma-globin gene expression was
  significantly reduced while beta-globin gene expression was virtually
  indistinguishable from that of wildtype controls. Navas et al. (2003)
  concluded that the GT6 motif is required for normal epsilon- and
  gamma-globin gene expression during embryonic erythropoiesis and for
  gamma-globin gene expression during definitive erythropoiesis in the
  fetal liver.
  Bottardi et al. (2005) noted that abnormal epigenetic regulation of gene
  expression contributes significantly to a variety of human pathologies
  including cancer. Deletion of HS2 at the human beta-globin locus control
  region can lead to abnormal epigenetic regulation of globin genes in
  transgenic mice. The authors used 2 HS2-deleted transgenic mouse lines
  as a model to demonstrate that heritable alteration of chromatin
  organization at the human beta-globin locus in multipotent hematopoietic
  progenitors can contribute to the abnormal expression of the beta-globin
  gene in mature erythroid cells. This alteration was characterized by
  specific patterns of histone covalent modifications that were inherited
  during erythropoiesis and, moreover, was plastic because it could be
  reverted by transient treatment with a histone deacetylase inhibitor.
  Bottardi et al. (2005) concluded that aberrant epigenetic regulation can
  be detected and modified before tissue-specific gene transcription.
  The eta locus is 1 of 5 ancient beta-related globin genes linked in a
  cluster, 5-prime--epsilon--gamma--eta--delta--beta--3-prime, that arose
  from tandem duplications (Koop et al., 1986). The eta locus was
  embryonically expressed in early eutherians and persisted as a
  functional gene in artiodactyls (e.g., goat), but became a pseudogene in
  proto-primates and was lost from rodents and lagomorphs. Sequence
  studies show that the goat eta gene is orthologous to the pseudogene
  located between the gamma and delta loci of primates and called
  psi-beta-1. (The Hb beta-1 pseudogene (psi-beta-1) can be symbolized
  HBBP or HBBP1.)
  (In the allelic variants that follow, as well as in the allelic variants
  listed under the other globin genes, the codon count begins with the
  first amino acid of the mature protein because a large portion of the
  variants were characterized on the basis of a protein rather than the
  gene itself. It is more customary for the count to begin with the
  methionine initiator codon as number one. Thus, the Hb S mutation
  (141900.0243) is designated glu6-to-val; in the gene based system of
  counting now used, it would be designated glu7-to-val. Some
  inconsistency is represented by the fact that some initiator mutations
  in the globin genes are indicated by a system counting from the
  initiator methionine; e.g., beta-thalassemia due to met1-to-ile
  Ciavatta et al. (1995) created a mouse model of beta-zero-thalassemia by
  targeted deletion of both adult beta-like globin genes, beta(maj) and
  beta(min), in mouse embryonic stem cells. Heterozygous animals derived
  from the targeted cells were severely anemic with dramatically reduced
  hemoglobin levels, abnormal red cell morphology, splenomegaly, and
  markedly increased reticulocyte counts. Homozygous animals died in
  utero; however, heterozygous mice were fertile and transmitted the
  deleted allele to progeny. The anemic phenotype was completely rescued
  in progeny derived from mating beta-zero-thalassemic animals with
  transgenic mice expressing high levels of human hemoglobin A. The
  authors suggested that beta-zero-thalassemic mice could be used to test
  genetic therapy for beta-zero-thalassemia and could be bred with
  transgenic mice expressing high levels of hemoglobin S to produce an
  improved mouse model of sickle cell disease.
  Hemoglobin disorders were among the first to be considered for gene
  therapy. Transcriptional silencing of genes transferred into
  hematopoietic stem cells, however, posed one of the most significant
  challenges to its success. If the transferred gene is not completely
  silenced, a progressive decline in gene expression as mice age often is
  encountered. These phenomena were observed to various degrees in mouse
  transplant experiments using retroviral vectors containing a human
  beta-globin gene, even when cis-linked to locus control region
  derivatives. Kalberer et al. (2000) investigated whether ex vivo
  preselection of retrovirally transduced stem cells on the basis of
  expression of the green fluorescent protein driven by the CpG island
  phosphoglycerate kinase (311800) promoter could ensure subsequent
  long-term expression of a cis-linked beta-globin gene in the erythroid
  lineage of transplanted mice. They observed that 100% of 7 mice
  engrafted with preselected cells concurrently expressed human
  beta-globin and green fluorescent protein in 20 to 95% of their red
  blood cells for up to 9.5 months posttransplantation, the longest time
  point assessed. This expression pattern was successfully transferred to
  secondary transplant recipients. In the presence of the beta-locus
  control region hypersensitivity site 2 alone, human beta-globin mRNA
  expression levels ranged from 0.15 to 20% with human beta-globin chains
  detected by HPLC. Neither the proportion of positive blood cells nor the
  average expression levels declined with time in translated recipients.
  Persons and Nienhuis (2000) discussed the background of the work by
  Kalberer et al. (2000), including position effect variegation (PEV).
  Both PEV and silencing mechanisms may act on a transferred globin gene
  residing in chromatin outside of the normal globin locus during the
  important terminal phases of erythroblast development when globin
  transcripts normally accumulate rapidly despite heterochromatization and
  shutdown of the rest of the genome.
  Ley et al. (1982) treated homozygous beta-plus-thalassemia in a
  42-year-old black American man with 5-azacytidine. An increase in
  hemoglobin concentration occurred. Hypomethylation of both the
  gamma-globin and the epsilon-globin gene was shown, as well as an
  increase in gamma-globin mRNA. Lucarelli et al. (1990) reviewed results
  from 222 consecutive patients in whom bone marrow transplantation was
  performed for thalassemia since 1983. The results were analyzed, in
  particular, in the 116 consecutive patients treated since June 1985. The
  allogeneic marrow came from HLA-identical donors, and the patients all
  had beta-thalassemia and were less than 16 years old. They concluded
  that bone marrow transplantation offered a high probability of
  complication-free survival, if the recipient did not have hepatomegaly
  or portal fibrosis.
  - Gene Therapy
  Gene therapy for beta-thalassemia is particularly challenging given the
  requirement for massive hemoglobin production in a lineage-specific
  manner and the lack of selective advantage for corrected hematopoietic
  stem cells. Compound beta-E/beta-0-thalassemia is the most common form
  of severe thalassemia in southeast Asian countries and their diasporas.
  The beta-E-globin allele (141900.0071) bears a point mutation that
  causes alternative splicing. The abnormally spliced form is noncoding,
  whereas the correctly spliced mRNA expresses a mutated beta-E-globin
  with partial instability. When this is compounded with a nonfunctional
  beta-0 allele, a profound decrease in beta-globin synthesis results, and
  approximately half of beta-E/beta-0-thalassemia patients are
  transfusion-dependent. The only available curative therapy is allogeneic
  hematopoietic stem cell transplantation, although most patients do not
  have a human leukocyte antigen (HLA)-matched, genoidentical donor, and
  those who do still risk rejection or graft-versus-host disease.
  Cavazzana-Calvo et al. (2010) showed that, 33 months after lentiviral
  beta-globin gene transfer, an adult patient with severe
  beta-E/beta-0-thalassemia dependent on monthly transfusions since early
  childhood had become transfusion-independent for the preceding 21
  months. Blood hemoglobin was maintained between 9 and 10 g/dL, of which
  one-third contained vector-encoded beta-globin. Most of the therapeutic
  benefit resulted from a dominant, myeloid-biased cell clone, in which
  the integrated vector caused transcriptional activation of HMGA2
  (600698) in erythroid cells with further increased expression of a
  truncated HMGA2 mRNA insensitive to degradation by let-7 microRNAs (see
  605386). Cavazzana-Calvo et al. (2010) suggested that the clonal
  dominance that accompanies therapeutic efficacy may be coincidental and
  stochastic or result from a hitherto benign cell expansion caused by
  dysregulation of the HMGA2 gene in stem/progenitor cells.
Allelic Variants:
  See Williamson et al. (1990).
  See Tentori et al. (1972), Chiancone et al. (1974), and Zhao et al.
  See Miyaji et al. (1966). As indicated by Corso et al. (1990), carriers
  of the mutation had been found in only 3 families, an American black, a
  Sicilian, and a Hungarian family, suggesting independent origins of the
  mutation. Corso et al. (1990) described another Sicilian family in which
  5 members carried Hb Agenogi; in 1, it was associated with
  beta-zero-thalassemia. The proposita, a 40-year-old woman with 2
  children, came to attention because of mild chronic anemia and biliary
  colic due to gallstones.
  Noguera et al. (2002) described Hb Agenogi in an Argentinian patient
  with Syrian and Hungarian ancestry. The mutation had previously been
  described in only 5 families, one of which was from Hungary.
  See Brimhall et al. (1975).
  See Lam et al. (1977) and Arends et al. (1987).
  See Mant et al. (1977), Stinson (1977), and Wong et al. (1978).
  See Marti et al. (1976).
  See Zak et al. (1974). Hebbel et al. (1978) used this hemoglobin to make
  ingenious observations on adaptation of humans to high altitudes.
  See Arcasoy et al. (1974) and Harano et al. (1981).
  May have arisen either through a second mutation in a person with Hb C
  or Hb N(Baltimore), or through crossing-over in a person who was
  heterozygous for both mutant hemoglobins. See Adams and Heller (1977).
  See Brown et al. (1976) and Moo-Penn et al. (1977).
  Unstable hemoglobin. See Hubbard et al. (1975) and Brennan et al.
  Brennan et al. (1986) described a 25-year-old man with congenital
  hemolytic anemia who was found to have the mutation of Hb Atlanta
  (beta75 leu-to-pro) and that of Hb Coventry (beta141 leu deleted) in the
  same beta-globin chain along with a normal beta-globin chain and a
  beta-globin chain with only the Hb Atlanta mutation. They stated that
  this is the sixth known example of 2 changes in 1 beta chain. They
  postulated that the doubly abnormal beta-globin was a beta-delta globin
  originating by a Lepore-type-mechanism. Brennan et al. (1992) found on
  restudy that leu141 was in fact not deleted but replaced by a novel
  amino acid which they suggested was hydroxyleucine; they proposed that
  the change resulted from posttranslational oxidation of leu141 as a
  consequence of perturbation of the haem environment caused by the
  leu75-to-pro mutation. The finding was consistent with the report of
  George et al. (1992) who found no evidence of deletion of leu141 in
  genomic DNA. The heterozygous patients have 3 hemoglobins: Hb A, Hb
  Atlanta, and Hb Atlanta-Coventry. The last 2 are the products of a
  single gene. A similar situation obtains with Hb Vicksburg
  (141900.0293), in which deletion of leu75 is not coded for in genomic
  DNA. Coleman et al. (1988) posited somatic mutation in that instance;
  however, a mechanism similar to that with Hb Atlanta-Coventry is
  See Moo-Penn et al. (1977).
  See Rahbar et al. (1979).
  See Wajcman et al. (1982). This is a high oxygen affinity hemoglobin
  See Schneider et al. (1977).
  See Strahler et al. (1983) and Blibech et al. (1986).
  See Kennedy et al. (1974).
  Galanello et al. (2004) reported the sixth occurrence of Hb Belfast, a
  change of codon 15 of the HBB gene from TGG (trp) to AGG (arg) (trp15 to
  arg; W15R), in a large Italian family with 9 affected members. The
  oxygen affinity of the isolated variant was increased. The clinical
  phenotype was silent or very mild, the only clinical finding being an
  intermittent moderate jaundice.
  See Efremov et al. (1973), Wilkinson et al. (1975), and Ruvidic et al.
  Akar et al. (1995) described a dual restriction enzyme digestion
  protocol for discriminating between Hb Beograd and Hb D (Los Angeles)
  (glu121 to gln) when they occur in the same population. Both of these
  variants migrate like Hb S on cellulose acetate electrophoresis. Hb O
  (Arab) (glu121 to lys; 141900.0202) represents no problem because that
  variant migrates differently on cellulose acetate electrophoresis. Also,
  the glu121-to-ter mutation (141900.0314) represents no problem because
  it is associated with a thalassemia phenotype. Other codon 121 mutations
  are Hb D (Neath) (glu121 to-ala; 141900.0445) and Hb St. Francis (glu121
  to gly; 141900.0412).
  Like Hb Kansas, this variant was associated with clinically evident
  cyanosis due to very low oxygen affinity (Nagel et al., 1976). (The
  hemoglobins M are not the only anomalous hemoglobins associated with
  See Hayashi et al. (1971), Adamson et al. (1972), Bunn et al. (1972),
  and Schmidt et al. (1976). See Hb Rainier.
  See Wajcman et al. (1976) and Miller et al. (1986).
  See Marinucci et al. (1981).
  See Hollender et al. (1969) and Bird et al. (1987).
  See Chen-Marotel et al. (1979).
  See Baudin-Chich et al. (1988).
  This variant is a cause of erythrocytosis. See Lokich et al. (1973).
  See Brennan et al. (1981), Rahbar et al. (1981), and Williamson et al.
  See Steadman et al. (1970) and Ohba et al. (1985).
  Rees et al. (1996) reinvestigated the patient who was the subject of the
  first description of idiopathic Heinz body anemia (140700) (Cathie,
  1952) and who was subsequently shown to have hemoglobin Bristol. Using
  both DNA and protein analysis, they showed that the original
  characterization of hemoglobin Bristol as val67 to asp was incorrect, in
  that a silent posttranslational modification of met to asp was mistaken
  for the primary mutation, which is, in fact, val67 to met. They also
  restudied 2 subsequent patients reported as having hemoglobin Bristol
  following protein sequencing in whom the same confusion occurred. They
  were able to describe a novel posttranslational modification in which
  the variant methionine amino acid residue is converted to an aspartate,
  probably catalyzed by the neighboring heme group and oxygen. The study
  emphasized the importance of analyzing both protein and DNA to
  characterize fully hemoglobin variants. Identification of the lesion as
  val67 to asp was made by Steadman et al. (1970).
  Although DNA codes for 20 primary amino acids, more than 140 different
  residues have been identified in proteins due to varied
  posttranslational modifications. Most are relatively simple reactions
  involving enzymatic modification of the site change of amino acids to
  enhance or determine the properties of the particular protein; these
  processes include acetylation, phosphorylation, hydroxylation, and
  glycation. There are also a number of posttranslational modifications of
  hemoglobin A, such as glycation and carbamoylation, but these are due
  mostly to nonspecific metabolic affects that alter the chemical
  environment of the hemoglobin, rather than direct results of the
  properties of the hemoglobin itself. Unstable hemoglobin variants are
  characterized by the reduced solubility of the hemoglobin tetramer in
  the red cell in peripheral blood. Most result from mutations of amino
  acids in key positions, for example, heme- or alpha-beta contact points.
  Mutations can also alter the structure of the molecule such that
  posttranslational changes can occur, either of the variant amino acid
  itself or of other residues exposed by changes in the conformation of
  the molecule. More rarely, so-called silent modifications occur, in
  which 1 primary amino acid is converted to another primary amino acid.
  This is what happened in the case of hemoglobin Bristol. The
  modification of beta-143 leu, such that it appears to be deleted on
  protein sequencing, in hemoglobin Atlanta-Coventry (141900.0013) is the
  result of posttranslational modification, possibly from leucine to
  hydroxyleucine, as a result of the primary mutation that effects the
  heme surface. The same apparent deletion of leu-149 is observed with Hb
  Christchurch (141900.0049) and with Hb Manukau (141900.0438), which is
  also a mutation of val67 (val67 to gly). There are 6 reported hemoglobin
  variants in which deamidation of an asparaginyl residue to an aspartate
  occurs as a silent posttranslational modification: these include
  hemoglobin Osler (141900.0211). The posttranslational change from
  methionine to aspartate was the first example to be described (Rees et
  al., 1996); the exact mechanism of the change is not clear.
  See Jones et al. (1977) and Stinson (1984).
  See Moo-Penn et al. (1980, 1988) and Ulukutlu et al. (1989). Negri
  Arjona et al. (1992) found a GCT (ala)-to-CCT (pro) mutation in codon
  138 in a 6-year-old Spanish girl with chronic hemolytic anemia requiring
  transfusion. The patient showed Heinz bodies. Her parents and a brother
  were normal, indicating that her disorder represented a new mutation.
  Tsoi et al. (1998) identified Hb Brockton in a 9-year-old Chinese boy
  with long-standing hemolysis. As in previous reports, the mutation
  occurred de novo. Tsoi et al. (1998) noted that the patient also had
  moyamoya disease (see 252350).
  Blouquit et al. (1989) demonstrated that hemoglobin Bruxelles, a
  beta-globin variant associated with severe congenital Heinz body anemia,
  has a deletion of 1 of the 2 adjacent phenylalanines, either phe41 or
  phe42. Other deletions affecting the phe41 or phe42 have been described.
  The nucleotide sequence of normal beta-globin mRNA is highly repetitive
  in the region of codons 41 to 46. Blouquit et al. (1989) suggested that
  the mutation originated through a frameshift mechanism.
  See Bradley et al. (1972), Lehmann (1973), and Weinstein et al. (1973).
  See Como et al. (1983). This is a high oxygen affinity hemoglobin
  See Turner et al. (1976) and Kobayashi et al. (1986).
  See Rieder et al. (1974), Ohba et al. (1985), and Efremov et al. (1987).
  See Itano and Neel (1950), Neel et al. (1953), Ranney et al. (1953),
  Hunt and Ingram (1959), Smith and Krevans (1959), Baglioni and Ingram
  (1961), River et al. (1961), and Fabry et al. (1981).
  By restriction haplotyping, Boehm et al. (1985) concluded that the
  beta-C-globin gene in blacks had a single origin followed by spread of
  the mutation to other haplotypes through meiotic recombination 5-prime
  to the beta-globin gene. On 22 of 25 chromosomes studied, they found the
  same haplotype (defined by 8 polymorphic restriction sites), a haplotype
  seen only rarely among beta-A-bearing chromosomes. The 3 exceptions
  showed identity to the typical beta-C allele in the 3-prime end of the
  beta-globin gene cluster. Trabuchet et al. (1991) presented haplotyping
  information suggesting a unicentric origin of the Hb C mutation in
  sub-Saharan Africa.
  Rapid detection of the sickle cell mutation is possible by amplifying
  the region of codon 6 by PCR and digesting the amplification product by
  a restriction endonuclease whose recognition site is abolished by the
  A-to-T mutation, the resulting abnormal fragment being detected with
  ethidium bromide staining after electrophoresis. Detection of the Hb C
  mutation is more difficult since no known restriction-endonuclease site
  is abolished or created by the mutation. Fischel-Ghodsian et al. (1990)
  described a rapid allele-specific PCR amplification technique that
  allowed detection of the Hb C mutation in an even shorter time span than
  the one required for detecting the Hb S mutation (141900.0243).
  To test the hypothesis that hemoglobin C protects against severe malaria
  (611162), Agarwal et al. (2000) conducted a study in the predominantly
  Dogon population of Bandiagara, Mali, in West Africa, where the
  frequency of Hb C is high (0.087) and that of Hb S is low (0.016). They
  found evidence for an association between HbC and protection against
  severe malaria in the Dogon population. Indeed, the data suggested less
  selection for the HbAS state in this group than for HbAC.
  In many children with sickle cell anemia (603903), functional asplenia
  develops during the first year of life and septicemia is the leading
  cause of death in childhood. The risk of septicemia in sickle cell
  anemia is greatest during the first 3 years of life and is reduced
  markedly by prophylactic penicillin therapy. Less is known about splenic
  dysfunction and the risk of overwhelming sepsis in children with SC
  disease, although functional asplenia has been documented by
  radionuclide liver-spleen scans in some adult patients (Ballas et al.,
  1982) and an elevated erythrocyte pit count, a finding that indicates
  functional asplenia in children with sickle cell anemia, also has been
  found in some children with SC disease (Pearson et al., 1985). Lane et
  al. (1994) reported 7 fatal cases of pneumococcal septicemia in children
  with SC disease. The earliest death occurred in a 1-year-old child who
  had cyanotic congenital heart; the other children were aged 3.5 to 15
  years. Only 1 child had received pneumococcal vaccine or prophylactic
  penicillin therapy. All 7 children had an acute febrile illness and
  rapid deterioration despite parenterally administered antibiotic therapy
  and intensive medical support. Erythrocyte pit counts in 2 patients were
  40.3 and 41.7%, respectively (normal, less than 3.6%). Autopsy findings
  in 5 cases included splenic congestion without infarction in 5,
  splenomegaly in 4, and bilateral adrenal hemorrhage in 3. Lane et al.
  (1994) concluded that pneumococcal vaccine should be administered in all
  children with SC disease. The routine use of prophylactic penicillin
  therapy in infants and children with SC disease remained controversial.
  The mutation in codon 6 of HBB in Hb S is GAG (glu) to GTG (val); the
  mutation in Hb C is GAG (glu) to AAG (lys). See also 141900.0039 and
  Modiano et al. (2001) performed a large case-control study in Burkina
  Faso on 4,348 Mossi subjects, and demonstrated that hemoglobin C is
  associated with a 29% reduction in risk of clinical malaria in Hb AC
  heterozygotes (P = 0.0008) and of 93% in Hb CC homozygotes (P = 0.0011).
  These findings, together with the limited pathology of Hb AC and Hb CC
  compared to the severely disadvantaged Hb SS and Hb SC genotypes and the
  low Hb S gene frequency in the geographic epicenter of Hb C, support the
  hypothesis that, in the long-term and in the absence of malarial
  control, Hb C would replace Hb S in central West Africa.
  Rihet et al. (2004) surveyed 256 individuals (71 parents and 185 sibs)
  from 53 families in Burkina Faso over 2 years and found that hemoglobin
  C carriers were found to have less frequent malaria attacks than AA
  individuals within the same age group (P = 0.01). Analysis of individual
  hemoglobin alleles yielded a negative association between Hb C and
  malaria attack (P = 0.00013). Analyses that took into account
  confounding factors confirmed the negative association of Hb C with
  malaria attack (P = 0.0074) and evidenced a negative correlation between
  Hb C and parasitemia (P = 0.0009).
  Fairhurst et al. (2005) reported a marked effect of hemoglobin C on the
  cell-surface properties of P. falciparum-infected erythrocytes involved
  in pathogenesis. Relative to parasite-infected normal erythrocytes (Hb
  AA), parasitized AC and CC erythrocytes showed reduced adhesion to
  endothelial monolayers expressing CD36 (173510) and intercellular
  adhesion molecule-1 (ICAM1; 147840). They also showed impaired rosetting
  interactions with nonparasitized erythrocytes, and reduced agglutination
  in the presence of pooled sera from malaria-immune adults. Abnormal
  cell-surface display of the main variable cytoadherence ligand, PfEMP-1
  (P. falciparum erythrocyte membrane protein-1), correlated with these
  findings. The abnormalities in PfEMP-1 display were associated with
  markers of erythrocyte senescence, and were greater in CC than in AC
  erythrocytes. Fairhurst et al. (2005) suggested that hemoglobin C might
  protect against malaria by reducing PfEMP1-mediated adherence of
  parasitized erythrocytes, thereby mitigating the effects of their
  sequestration in the microvasculature.
  Recombinational hotspots are a ubiquitous feature of the human genome,
  occurring every 60 to 200 kb, and likely contribute to the observed
  pattern of large haplotypic blocks punctuated by low linkage
  disequilibrium (LD) over very short (1 to 2 kb) distances. Recombination
  breaks up ancestral LD and produces new combinations of alleles on which
  natural selection can act. Positive selection increases the frequency of
  beneficial mutations, creating LD via genetic 'hitchhiking.' The
  beta-globin hotspot spans approximately 1 kb and is located
  approximately 500 bp from the selected site at the beta-globin gene. The
  close proximity of these beta-globin regions allowed Wood et al. (2005)
  to empirically examine the signature of selection across a region that
  recombines at a rate 50 to 90 times higher than the genomic average of
  1.1 cM/Mb. Early studies of the HbC polymorphism suggested that this
  allele was, like the hemoglobin S allele (141900.0243), also subject to
  balancing selection (Allison, 1954). Subsequently, it was shown that HbC
  provides protection against Plasmodium falciparum without significantly
  reducing fitness, indicating that this allele is increasing in frequency
  as a result of positive directional selection (Agarwal et al., 2000;
  Modiano et al., 2001; Hedrick, 2004; Rihet et al., 2004). Because the
  African HbC allele rarely exceeds frequencies of 20% and is
  geographically concentrated in central West Africa, it is thought that
  this mutation is very young. Wood et al. (2005) examined the extent of
  LD surrounding the African HbC allele to estimate its age and the
  strength of selection acting on this mutation and tested the hypothesis
  that the beta-globin recombinational hotspot decouples the selected HbC
  allele from nearby upstream regions. They estimated that the HbC
  mutation originated less than 5,000 years ago and that selection
  coefficients are between 0.04 and 0.09. Despite strong selection and the
  recent origin of the HbC allele, recombination (crossing-over or gene
  conversion) is observed within 1 kb 5-prime of the selected site on more
  than one-third of the Hb chromosomes sampled. The rapid decay in LD
  upstream of the HbC allele demonstrates the large effect the beta-globin
  hotspot has in mitigating the effects of positive selection on linked
  variation, in other words a reduction in 'hitchhiking.'
  Modiano et al. (2008) adopted 2 partially independent haplotypic
  approaches to study the Mossi population in Burkina Faso, where both the
  HbS and HbC alleles are common. They showed that both alleles are
  monophyletic, but that the HbC allele has acquired higher
  recombinatorial and DNA slippage haplotypic variability or linkage
  disequilibrium decay and is likely older than HbS. Modiano et al. (2008)
  inferred that the HbC allele has accumulated mainly through recessive
  rather than a semidominant mechanism of selection.
  Gouagna et al. (2010) used cross-sectional surveys of 3,739 human
  subjects and transmission experiments involving 60 children and over
  6,000 mosquitoes in Burkina Faso, West Africa, to test whether the HBB
  variants HbC and HbS, which are protective against malaria, are
  associated with transmission of the parasite from the human host to the
  Anopheles mosquito vector. They found that HbC and HbS were associated
  with significant 2-fold in vivo (P = 1.0 x 10(-6)) and 4-fold ex vivo (P
  = 7.0 x 10(-5)) increases of parasite transmission from host to vector.
  In addition, the HbC allele was consistently associated with higher
  gametocyte rate.
  Red cells containing this hemoglobin, with 2 mutations in the HBB gene,
  sickle. The sickling is the result, of course, of the glu-to-val
  mutation, which is not counteracted by the asp73-to-asn mutation. It is
  called Hb C (not S) because of its electrophoretic properties. See
  Pierce et al. (1963), Bookchin et al. (1966, 1968, 1970), and Lang et
  al. (1972).
  As in the other cases of doubly substituted beta chains, either double
  mutation or intracistronic recombination in a genetic compound would
  explain the observation. This hemoglobin sickles because of its
  glu6-to-val substitution, but is called Hb C (not S) because of its
  electrophoretic properties, which are those of classic Hb C. See
  Goossens et al. (1975) and Hassan et al. (1977).
  See Cohen et al. (1973), Cotten et al. (1973), and Honig et al. (1980).
  See Rucknagel (1986); hemoglobin Motown was formerly thought to be a
  change at beta 127 (Gibb, 1981). See Ohba et al. (1975); hemoglobin
  Tokuchi was formerly thought to be a substitution of tyrosine for
  histidine at beta 2 (Shibata et al., 1963).
  See Wilkinson et al. (1975) and Zhao et al. (1990).
  See Ahern et al. (1976) and Ali et al. (1988).
  See Garel et al. (1975).
  Walker et al. (2003) described heterozygosity for Hb Castilla in an
  8-month-old boy with persistent hemolytic anemia.
  Dash et al. (1989) described Hb Chandigarh in a 35-year-old carrier of
  beta-thalassemia who was the father of a child diagnosed to have
  homozygous beta-thalassemia. At that time, the patient was normocytic
  with normal values of hemoglobin, PCV, and RBC count. Two other
  hemoglobin variants with substitutions at asp94 had been described: Hb
  Barcelona (asp94 to his; 141900.0016) and Hb Bunbury (asp94 to asn;
  141900.0035), both of which were described as high oxygen affinity Hb
  variants, with or without erythrocytosis. Dash and Das (2004) reported
  on the same patient observed 15 years later. He then had marked
  hepatosplenomegaly and was found to have polycythemia. The asp94 residue
  was known to form a salt bridge between its carboxyl group and the
  imidazolium ion of the histidine residue at the C terminus. The loss of
  this salt bridge appears to destabilize the deoxy structure and shift
  the equilibrium from the deoxy to the oxy configuration.
  See Rochette et al. (1984).
  See Yeager et al. (1983). (Hb Hammersmith is beta-42 phe to ser. Despite
  the functional and structural similarities, the clinical manifestations
  of Hb Cheverly are much milder than those of Hb Hammersmith.)
  See Shih et al. (1987). Hb Chico has diminished oxygen affinity
  (Bonaventura et al., 1991). Its oxygen-binding constant is about half
  that of normal. Bonaventura et al. (1991) presented data on the
  molecular basis of this altered property.
  See Carrell (1970).
  See Rahbar et al. (1984) and Kutlar et al. (1989). De Angioletti et al.
  (1992) detected Hb City of Hope by reversed phase high performance
  liquid chromatography in an asymptomatic carrier in Naples. The
  gly69-to-ser substitution, identified by fast atom bombardment mass
  spectrometry, was shown to be due to a TGG-to-TGA substitution by DNA
  sequencing. The mutation was associated with RFLP haplotype 9, instead
  of haplotype 1, as previously reported.
  See Wajcman et al. (1975).
  De Angioletti et al. (2002) described the comparable mutation in the
  delta chain of hemoglobin A, designated HBA2-Monreale (142000.0038).
  See Boissel et al. (1981), Fabritius et al. (1985), and Ohba et al.
  See Williamson et al. (1983).
  See Moo-Penn (1981).
  The proband was a child who appeared to have 3 different beta chains in
  addition to the delta chain of Hb A2 and the gamma chain of Hb F (Casey
  et al., 1976, 1978). The child had Hb Sydney (beta 67 val-to-ala) and
  deletion of beta 141 leu. These were in different beta genes. The
  presence of 3 beta genes suggested to Lehmann (1978) that the beta
  Coventry chain is in fact a beta-delta fusion chain. Fay et al. (1993)
  offered the explanation of posttranslational modification of leu-141,
  probably a conversion to hydroxyleucine, which was not detected by
  standard amino acid analysis and sequencing methods. Of interest was the
  finding that not only Hb Sydney but also another substitution at the
  same codon, val67-to-gly in Hb Manukau, showed this feature. Hemoglobin
  Coventry was also found in association with Hb Atlanta (leu75-to-pro)
  This variant was named for Fort Worth, Texas. Polycythemia is produced.
  One member of the family was treated with P32 for presumed polycythemia
  rubra vera (Schneider, 1978; Schneider et al., 1979). This and about 40
  other hemoglobin variants are associated with erythrocytes. See Perutz
  et al. (1984).
  HBB, 2-BP INS, CODON 144, FS
  This hemoglobin was found in an asymptomatic woman with a compensated
  hemolytic state due to an unstable hemoglobin variant (Bunn et al.,
  1975). The hemoglobin had an abnormally long beta chain that, starting
  at amino acid 144, had the following sequence:
  lys-ser-ile-thr-lys-leu-ala-phe-leu-leu-ser-asn-phe-tyr-COOH. This is
  the first Hb A variant known to contain isoleucine. Bunn et al. (1975)
  concluded that Hb Cranston probably arose by nonhomologous crossing-over
  between 2 normal beta chain genes, resulting in the insertion of 2
  nucleotides (AG) at position 144, to produce a frame shift. Hb Wayne is
  thought to be a frame shift mutation involving the alpha chain. Hb Tak
  is another hemoglobin with abnormally long beta chain. Hb Constant
  Spring, Hb Koya Dora, and Hb Icaria are hemoglobins with abnormally long
  alpha chains. See Shaeffer et al. (1980).
  See Maniatis et al. (1979).
  Christopoulou et al. (2004) identified a 1368G-C transversion in exon 3
  of the beta-globin gene, resulting in an ala129-to-pro (A129P)
  substitution. Both the proband and her mother, who were found to be
  heterozygous for Hb Crete, presented with mild microcytic anemia and
  normal hemoglobin A2 levels and iron metabolism indices.
  Erythrocytosis results. See Thillet et al. (1976) and Poyart et al.
  See Wade et al. (1967).
  See de Pablos et al. (1987).
  See Watson-Williams et al. (1965).
  See Rohe et al. (1972), Rahbar (1973), and Serjeant et al. (1982).
  See Elion et al. (1973) and Ren et al. (1988).
  Among 598 children from the Berber population of the Mzab, Merghoub et
  al. (1997) found Hb C and Hb D-(Ouled Rabah) in the same gene frequency
  (0.015). Hb D-(Ouled Rabah) is considered a private marker of the Kel
  Kummer Tuaregs. Haplotype analysis suggested a single origin of the Hb D
  mutation. Genetic markers calculated from blood group data clustered
  Mozabites and Tuaregs with the other Berber-speaking groups,
  Arabic-speaking populations being more distant. However, they found no
  specific relationship between the Mozabites and Kel Kummers. Tuaregs in
  general exhibit features that tend to differentiate them from other
  Berber-speaking groups. Merghoub et al. (1997) concluded that Hb
  D-(Ouled Rabah) may be specific for Berber-speaking populations.
  Merghoub et al. (1997) noted that the origin of the Berber people is not
  clearly established. North Africa was peopled around the sixteenth
  millennium B.C.; transition to agriculture occurred around 9500 to 7000
  B.C., spreading from the Near East to Egypt. The Arab invasion in the
  seventh and eighth centuries brought Islamization and dispersal of the
  Berber culture. Present-day populations of North Africa are mostly
  Arabic-speaking, whatever their remote origin. Berbers, however, with
  their languages and customs, still live in small niches of northern
  Morocco and Algeria, and in some northern oases of the Sahara, including
  those of the Mzab (Algeria). The Tuaregs also speak Berber languages.
  They inhabit the south of the Sahara and have been involved for
  centuries in trans-Saharan trade. Tuaregs have their own culture that
  probably diverged from the Berber world through isolation.
  See Benzer et al. (1958), Bowman and Ingram (1961), Stout et al. (1964),
  Schneider et al. (1968), Lehmann and Carrell (1969), Ozsoylu (1970),
  Imamura and Riggs (1972), Bunn et al. (1978), Trent et al. (1982),
  Worthington and Lehmann (1985), Husquinet et al. (1986), and Harano et
  al. (1987). Hemoglobin D (Punjab) is common worldwide. It is the most
  frequent abnormal hemoglobin in Xinjiang Uygur Autonomous Region of
  China (Li et al., 1986). Zeng et al. (1989) used the PCR method for
  population studies of this variant. Using PCR and direct sequencing,
  Schnee et al. (1990) demonstrated the predicted G-to-C substitution in
  codon 121.
  See Labossiere et al. (1972), Powars et al. (1977), and Shulman and Bunn
  See Moo-Penn et al. (1978).
  See Gacon et al. (1977).
  Kamel et al. (1985) investigated a Qatari family with an
  electrophoretically fast-moving hemoglobin that they found contained an
  abnormal beta chain with the sequence met-glu-his-leu at the NH2-end.
  Substitution of glutamic acid for valine at beta 1 apparently prevented
  removal of the initiator methionine. The methionine was blocked by a
  molecule not completely identified. No clinical consequences were
  observed in heterozygotes.
  See Beutler et al. (1974).
  See Hunt and Ingram (1961), Shibata et al. (1962), Blackwell et al.
  (1970), Fairbanks et al. (1980), Benz et al. (1981), and Kazazian et al.
  (1984). Orkin et al. (1982) reported the complete nucleotide sequence of
  a beta-E-globin gene. They found a GAG-to-AAG change in codon 26 as the
  only abnormality. Expression of the beta-E gene was tested by
  introducing it into HeLa cells. Two abnormalities of RNA processing were
  shown: slow excision of intervening sequence-1 and alternative splicing
  into exon 1 at a cryptic donor sequence within which the codon 26
  nucleotide substitution resides. Antonarakis et al. (1982) used the
  Kazazian haplotype approach of analyzing DNA polymorphisms in the
  beta-globin cluster to present evidence that the beta-E mutation
  occurred at least twice in Southeast Asia, the mutation being G-to-A at
  the first nucleotide of codon 26. Thein et al. (1987) demonstrated that
  the GAG-to-AAG change could be recognized by the restriction enzyme MnlI
  which cleaves DNA at the sequence 3-prime-GGAG-5-prime. Rey et al.
  (1991) described SE disease in 3 black American children of Haitian
  origin. They pointed out that the disorder is probably more benign than
  SC disease, SO(Arab) disease, and SC(Harlem) disease, all of which have
  increased risk of the complications of sickling including pneumococcal
  Rees et al. (1996) reported a girl homozygous for Hb E with severe
  anemia and anisopoikilocytosis, who was also homozygous for pyrimidine
  5-prime nucleotidase deficiency (P5N; 266120). In erythrocytes deficient
  for P5N the stability of the Hb E was decreased.
  Hemoglobin E is very common in parts of Southeast Asia. Chotivanich et
  al. (2002) examined the possible protective role of Hb E and other
  prevalent inherited hemoglobin abnormalities against malaria (611162) in
  Thailand. They assessed the effect of Hb E by means of a mixed
  erythrocyte invasion assay. In vitro, starting at 1% parasitemia,
  Plasmodium falciparum preferentially invaded normal (Hb AA) compared to
  abnormal hemoglobin red blood cells, including those heterozygous and
  homozygous for Hb E. The heterozygote Hb AE cells differed markedly from
  all the other cells tested, with invasion restricted to approximately
  25% of the red blood cells. Despite their microcytosis, AE heterozygous
  cells were functionally relatively normal in contrast to the red blood
  cells from the other hemoglobinopathies studied. Chotivanich et al.
  (2002) interpreted these findings as suggesting that Hb AE erythrocytes
  have an unidentified membrane abnormality that renders most of the red
  blood cell population relatively resistant to invasion by P. falciparum.
  This would not protect from uncomplicated malaria infections but would
  prevent the development of heavy parasite burdens and was considered
  consistent with the 'Haldane hypothesis' of heterozygote protection
  against severe malaria for Hb E.
  The Hb E variant is concentrated in parts of Southeast Asia where
  malaria is endemic, and Hb E carrier status confers some protection
  against Plasmodium falciparum malaria. To examine the effect of natural
  selection on the pattern of linkage disequilibrium (LD) and to infer the
  evolutionary history of the Hb E variant, Ohashi et al. (2004) analyzed
  biallelic markers surrounding the Hb E variant in a Thai population.
  Pairwise LD analysis of Hb E and 43 surrounding biallelic markers
  revealed LD of Hb E extending beyond 100 kb, whereas no LD was observed
  between non-Hb E variants and the same markers. The inferred haplotype
  network suggested a single origin of the Hb E variant in the Thai
  population. Forward-in-time computer simulations under a variety of
  selection models indicated that the Hb E variant arose 1,240 to 4,440
  years ago. Thus, the Hb E mutation occurred recently and allele
  frequency increased rapidly. The study demonstrated that a high
  resolution LD map across the human genome can detect recent variants
  that have been subjected to positive selection.
  The highest frequencies of the Hb E gene in large population samples,
  approximately 0.3, had been observed in the southern part of
  northeastern Thailand. Even higher frequencies were observed by Flatz et
  al. (2004) in Austroasiatic populations in southern Laos. One frequency
  was as high as 0.433 in a population of Sekong Province.
  As in other areas of Southeast Asia, hemoglobin E is a very common
  hemoglobin variant in India, where the highest prevalence of hemoglobin
  E has been observed in the northeastern regions. In West Bengal, carrier
  frequency varies from 5 to 35% in different subpopulations, whereas in
  Assam and Meghalaya, the heterozygous frequency ranges from 27 to 51%.
  Individuals heterozygous for hemoglobin E have normal or near-normal
  mean corpuscular volume (MCV) with 27 to 31% of the abnormal Hb in
  peripheral blood. Homozygosity for hemoglobin E is commonly benign,
  characterized by mild hypochromic microcytic anemia with the presence of
  target cells. Edison et al. (2005) observed hyperbilirubinemia among
  patients with homozygosity for the hemoglobin E gene in the Indian
  population, with jaundice being the major complaint at presentation. A
  study of UGT1A1 gene polymorphism showed that the variant TA(7) in the
  promoter region of the UGT1A1 gene (191740.0011) was associated with
  hyperbilirubinemia in homozygous HbE patients.
  The role of the TA(7) polymorphism of UGT1A1 in the determination of
  jaundice and gallstones in hemoglobin E beta-thalassemia had been
  pointed out by Premawardhena et al. (2001) in studies from Sri Lanka.
  The same group (Premawardhena et al., 2003) studied the global
  distribution of length polymorphisms of the promoters of the UGT1A1
  gene. They found that homozygosity for the TA(7) allele occurred in 10
  to 25% of the populations of Africa and the Indian subcontinent, with a
  variable frequency in Europe. It occurred at a much lower frequency in
  Southeast Asia, Melanesia, and the Pacific Islands, ranging from 0 to
  5%. African populations showed a much greater diversity of length
  alleles than other populations. These findings defined those populations
  with a high frequency of hemoglobin E beta-thalassemia and related
  disorders that are at increased risk for hyperbilirubinemia and gall
  bladder disease. Beutler et al. (1998) had suggested that the wide
  diversity in the frequency of the UGT1A1 promoter alleles might reflect
  a balanced polymorphism mediated through the protective effect of
  bilirubin against oxidative damage.
  See Vella et al. (1967) and Gonzalez-Redondo et al. (1987). Gurgey et
  al. (1990) found compound heterozygosity for this mutation and
  beta-thalassemia of type IVS1-6 (141900.0360). Igarashi et al. (1995)
  identified Hb E-Saskatoon in a Japanese male. Igarashi et al. (1995)
  reported what they stated was the first case of Hb-E (Saskatoon) in a
  Japanese male.
  Birben et al. (2001) described Hb E-Saskatoon in homozygous state in a
  30-year-old Turkish woman. The consanguineous parents were heterozygotes
  for the abnormal hemoglobin. The heterozygous son of the proband had
  mild anemia; physical examination of the child and family members
  revealed no abnormalities. The parameters of routine hematologic studies
  were within normal limits.
  See Labossiere et al. (1971). Landin et al. (1996) pointed out that 2
  nucleotide substitutions in codon 50, either ACT to AAA, or ACT to AAG,
  would be required to produce this amino acid substitution. The same is
  true for the amino acid substitutions in Hb Bristol (141900.0030) and Hb
  Beckman (141900.0442) among the beta-globin variants and Hb J-Kurosh
  (141800.0066), an alpha-globin variant.
  In a Spanish female with mild hemolytic anemia, Villegas et al. (1989)
  demonstrated this mildly unstable hemoglobin.
  See Moo-Penn et al. (1976). In 5 apparently, unrelated Spanish adults,
  Qin et al. (1994) found a fast-moving hemoglobin variant and observed a
  GGC-to-GAC mutation at codon 119 which had previously been identified as
  the abnormality in Hb Fannin-Lubbock. In addition, however, they found a
  GTC-to-CTC change at codon 111 which led to a val-to-leu substitution.
  Protein analysis in one of the individuals confirmed that the 2
  mutations were located on the same chromosome. Qin et al. (1994)
  suggested that some other known variants may carry an additional
  mutation that results in an electrophoretically silent amino acid
  substitution which may, however, have an effect on the physicochemical
  properties of the protein. In the case of Hb Fannin-Lubbock, it appeared
  likely that the val111-to-leu substitution, rather than the
  gly119-to-asp replacement, was the cause of the instability of the
  variant. The Hb Fannin-Lubbock variant in these Spanish families had a
  normal oxygen affinity.
  Deletion of val23 from otherwise normal beta chain probably occurred
  through triplet deletion resulting from unequal crossing-over between 2
  normal beta loci in 1 parent of the proband. Two of 3 living children of
  the proband also had the abnormal hemoglobin, which was accompanied by
  slight cyanosis in all 3 and by a hemolytic process in the proband. See
  Jones et al. (1966) and Horst et al. (1988).
  See Harano et al. (1990).
  See Hidaka et al. (1988).
  There is no clinical or hematologic abnormality in the homozygote. See
  Edington et al. (1955), Gammack et al. (1961), Lehmann et al. (1964),
  and Milner (1967).
  See Sick et al. (1967), Schiliro et al. (1981), and Chen et al. (1985).
  See Schneider et al. (1964), Bowman et al. (1967), Vella et al. (1967),
  Blackwell et al. (1967), Blackwell et al. (1968), Blackwell et al.
  (1969), Ohba et al. (1978), Niazi et al. (1981), and Dincol et al.
  See Giardina et al. (1978).
  See Bowman et al. (1962, 1964).
  See Blackwell et al. (1972).
  See Blackwell et al. (1970).
  This hemoglobin oxy was first described in a family of Calabrian origin
  by Schwartz et al. (1957). The molecular defect was demonstrated by Hill
  et al. (1960). Brancati et al. (1989) reported a case of homozygosity in
  a healthy male with normal hematologic findings. See Hill and Schwartz
  (1959), Ricco et al. (1974), Wilson et al. (1980), and Schiliro et al.
  See Blackwell et al. (1969), Imai et al. (1970), Kaufman et al. (1975),
  Welch (1975) and Romero et al. (1985). Schiliro et al. (1991) found this
  abnormal hemoglobin in 4 members from 2 generations of a Sicilian
  See Blackwell et al. (1969), Zeng et al. (1981), and Landman et al.
  See Blackwell and Liu (1968).
  See Chen et al. (1985).
  See Marinucci et al. (1977).
  See Como et al. (1984).
  Unstable hemoglobin. See Sansone et al. (1967), Labie et al. (1972),
  Kendall et al. (1979), Shibata et al. (1980), and Hopmeier et al.
  See Baklouti et al. (1987).
  HBB, 15-BP DEL
  Deletion of amino acid residues 93-97 inclusive of beta chain probably
  through unequal crossing over. This unstable hemoglobin also has absence
  of half of the normal complement of heme. Other unstable hemoglobins
  include Hb Zurich, Hb Koln, Hb Geneva, Hb Sydney, Hb Hammersmith and Hb
  Sinai. (It is possible that the deletion is 91-95 or 92-96 rather than
  93-97.) See Bradley et al. (1967) and Rieder and Bradley (1968). See Hb
  Koriyama (141900.0152).
  See Altay et al. (1976) and Huisman et al. (1986).
  By isoelectric focusing (IEF) of red cell hemolysates, this hemoglobin
  variant simulates glycated hemoglobin (Hb A1c). This is the first
  mutation discovered at beta 116. It was first found in a 6-year-old boy
  with diabetes mellitus; 5 nondiabetic members of the family had the same
  hemoglobin variant (Blanke et al., 1988). (Hafnia is Latin for
  During neonatal screening in Belgium, Cotton et al. (2000) found a
  newborn of Brazilian origin with Hb Hafnia. Both he and his mother were
  heterozygous for a CAT-to-CAA transversion at codon 116. Both were
  clinically and hematologically normal.
  See Rahbar et al. (1975).
  Akar et al. (2003) described the first observation of homozygous Hb
  Hamadan in a Turkish family. In this family 1 member was a compound
  heterozygote for Hb Hamadan and beta-thalassemia due to a -29G-A
  promoter mutation. This was said to be a novel thalassemia mutation. See
  141900.0379 for a previously reported form of thalassemia due to a
  -29A-G promoter mutation. Neither homozygous Hb Hamadan nor a
  combination with beta-thalassemia appeared to have clinical
  See Manca et al. (1987) and Wong et al. (1984). Manca et al. (1992)
  described an easy PCR-based method for demonstration of the mutation.
  They demonstrated the predicted G-to-A transition at codon 11 which
  abolishes a MaeIII restriction site. This mutation, which is rather
  common among Sardinians, involves one of the 5 CpG dinucleotides of the
  beta-globin gene.
  The normal phenylalanine at this site apparently 'stabilizes' the heme
  with which it is in contact. The substitution of serine leads to severe
  Heinz body hemolytic anemia. See Dacie et al. (1967), Ohba et al.
  (1975), and Rahbar et al. (1981). Dianzani et al. (1991) demonstrated a
  de novo phe42-to-ser mutation using the chemical cleavage of mismatch
  method (CCM) of Cotton et al. (1988). The responsible substitution was a
  TTT-to-TCT change. The report of rare cases of this hemoglobinopathy in
  different ethnic groups also supports the occurrence of independent
  See Blouquit et al. (1985).
  Hb Heathrow is a cause of erythrocytosis because of increase in oxygen
  affinity. The mutation occurs in the same codon as that in Hb Saint
  Nazaire (141900.0436).
  See White et al. (1973).
  This is a cause of familial erythrocytosis. See Ikkala et al. (1976).
  See Blouquit et al. (1976) and Bardakdjian et al. (1987).
  See Miyaji et al. (1968).
  Heterozygotes have about 60% hemoglobin Hikari. See Shibata and Iuchi
  (1962) and Shibata et al. (1964).
  This hemoglobin was found in a diabetic because its N-terminal glycation
  was about 3 times that of the normal (Ohba et al., 1986).
  See Moo-Penn et al. (1989).
  See Yanase et al. (1968) and Ohba et al. (1983).
  Associated with increased oxygen affinity, decreased Bohr effect, and
  erythremia. (The substitution was formerly thought to be at residue
  143.) See Hamilton et al. (1969) and Perutz et al. (1971).
  See Miyaji et al. (1968), Brittenham et al. (1978), Ohba et al. (1981),
  and Arends et al. (1985).
  See Minnich et al. (1965), Steinberg et al. (1974, 1976), Charache et
  al. (1979), Harano et al. (1983), Martinez and Colombo (1984), and Enoki
  et al. (1989). In a Thai Mien family, Pillers et al. (1992) observed Hb
  Hope in compound heterozygous state with Hb E. Previous reports of Hb
  Hope had involved predominantly black Americans, blacks who lived in
  Cuba, or natives of Mali who lived in France.
  Ingle et al. (2004) analyzed interactions of Hb Hope with Hb S
  (141900.0243), other variant hemoglobins, and thalassemia.
  See Iuchi et al. (1978) and Shibata et al. (1980). Plaseska et al.
  (1991) observed this mutation, due to a GAG-to-CAG change at codon 43,
  in a Yugoslavian family.
  See Blouquit et al. (1981).
  See Boulton et al. (1970), Lacombe et al. (1987), and Wilkinson et al.
  Hamaguchi et al. (2000) reported the first case of hemoglobin I (High
  Wycombe) in Japan. It was suspected because of a discrepancy between
  blood glucose status and glycated hemoglobin measurements in a
  55-year-old diabetic female.
  See Rosa et al. (1969) and Labie et al. (1971).
  Adams et al. (1978, 1979) studied father and daughter with a clinical
  picture of beta-thalassemia which was due to labile beta-chains
  resulting in Heinz body formation in normoblasts. The changes in the
  beta-chains were posttranslational. Baiget et al. (1986) and De Biasi et
  al. (1988) described 2 new families with the cys112-to-arg mutation. In
  these families the carriers were not anemic, had normal chromic and
  normocytic red cells, and displayed only mild reticulocytosis. This
  prompted Coleman et al. (1991) to restudy the original family with the
  finding that the mutation in fact was leu106-to-arg. In order to avoid
  confusion, they renamed the original mutation Hb Terre Haute (see
  One patient had an apparent new mutation; the father was 41 years old
  and the mother 36 at the patient's birth (Aksoy et al. (1972)). See
  Beuzard et al. (1972) and Aksoy and Erdem (1979).
  De Weinstein et al. (2000) described this hemoglobin variant in a
  36-year-old Argentinian female of Spanish-Portuguese origin. She
  presented with chronic hemolytic anemia, jaundice, splenomegaly, and
  gallstones from childhood. She required blood transfusion during her
  only pregnancy at the age of 23. She underwent splenectomy and
  cholecystectomy when she was 33 years old. Her 13-year-old son also
  presented with chronic hemolytic anemia, jaundice, and splenomegaly. It
  was the third observation of this hemoglobin variant. In the first 2
  cases, origination was by de novo mutation. This was the first case in
  which the precise DNA change was identified: codon 92 was changed from
  CAC (his) to CAG (gln).
  See Adams et al. (1975, 1978).
  See Elion et al. (1979) and Harano et al. (1990).
  See Huisman et al. (1986).
  See Williamson et al. (1987).
  Fast hemoglobin. See Went and MacIver (1959), Gammack et al. (1961),
  Sydenstricker et al. (1961), Huisman and Sydenstricker (1962),
  Weatherall (1964), Chernoff and Perillie (1964), Wilkinson et al.
  (1967), Wong et al. (1971), and Musumeci et al. (1979).
  See Clegg et al. (1966), Blackwell and Liu (1966), Pootrakul et al.
  (1967), Blackwell et al. (1970), and Iuchi et al. (1981).
  See Garel et al. (1976).
  See Tentori (1974) and Marinucci et al. (1979).
  See Romain et al. (1975). This hemoglobin was discovered in a 2-year-old
  black child from Chicago, who was hospitalized for iron deficiency
  anemia. The second case was reported in a Spanish family by Arrizabalaga
  et al. (1998).
  See Bardakdjian et al. (1988).
  See Boissel et al. (1982).
  The first reported cases were in a Cuban family of African ancestry
  (Martinez et al., 1977). Wajcman et al. (1988) described a case from
  Benin in Nigeria. Also see Zhu et al. (1988) and Sciarratta et al.
  (1990). Yamagishi et al. (1993) identified this mutation in a Japanese
  family during assay of glycated hemoglobins by ion exchange high
  performance liquid chromatography. No anemia or hemolysis was observed
  in the affected members of the family, although one member had a
  decreased haptoglobin value.
  See Gammack et al. (1961), Rahbar et al. (1967), and Delanoe-Garin et
  al. (1986). Bircan et al. (1990) observed compound heterozygosity of
  this variant with Hb N (Baltimore) (141900.0188).
  See Blackwell et al. (1971) and Blackwell et al. (1972). Chang et al.
  (1992) described a new RFLP created by this substitution.
  See Djoumessi et al. (1981).
  See Wajcman et al. (1977) and Prior et al. (1989).
  See Lin et al. (1992).
  See Salomon et al. (1965) and Sick et al. (1967).
  Plaseska-Karanfilska et al. (2000) described Hb Rambam in a family in
  Argentina. It was combined in compound heterozygous state with a form of
  beta-zero-thalassemia due to deletion of 2 nucleotides (CT) from codon
  5. The latter mutation had been found among Bulgarian, Turkish, Greek,
  Macedonian, North African, and Middle Eastern populations, and in some
  populations of the Indian subcontinent.
  See Ricco et al. (1974).
  See Blackwell et al. (1969).
  See Lu et al. (1983).
  See Jones et al. (1990).
  Hb Johnstown, caused by a change of codon 109 in exon 3 of the HBB gene
  from GTG (val) to CTG (leu) (val109 to leu), is a high oxygen affinity
  hemoglobin variant. Feliu-Torres et al. (2004) identified Hb Johnstown
  in association with beta-zero-thalassemia of the IVS1AS-1G-A
  (141900.0356) type in an 8-year-old girl referred because of
  erythrocytosis and a left-shifted oxygen dissociation curve. The mother
  was found to be heterozygous for the Hb variant and the father was a
  beta-zero-thalassemia carrier. This Hb variant had normal
  electrophoresis. The erythrocytosis and low values for actual P50 due to
  Hb Johnstown were more marked due to the coinheritance of the
  See Allan et al. (1965).
  See Allan et al. (1965). Castagnola et al. (1990) found this variant in
  an Italian family.
  See Allan et al. (1965) and Ringelhann et al. (1971).
  Codon 30 (for arginine) is interrupted between the second and third
  nucleotide by the first intervening sequences of 130 nucleotides.
  Modifications of the consensus sequence of the donor-splice site of IVS1
  will affect the process of splicing. In hemoglobin Monroe, the G-to-C
  mutation occurred at a nucleotide position adjacent to the GT
  dinucleotide required for splicing; this substitution would be expected
  to cause greatly decreased splicing and severe beta-plus-thalassemia, as
  was observed in the family reported by Gonzalez-Redondo et al. (1989).
  In a Mediterranean type of beta-plus-thalassemia, Vidaud et al. (1989)
  found a G-to-C transversion in codon 30 that altered both beta-globin
  pre-mRNA splicing and the structure of the hemoglobin product.
  Presumably, this G-to-C transversion at position -1 of intron 1 reduced
  severely the utilization of the normal 5-prime splice site, since the
  level of the arg-to-thr mutant hemoglobin (designated hemoglobin
  Kairouan) was very low in heterozygotes (2% of total hemoglobin). Since
  no natural mutations of the guanine located at position -1 of the
  CAG/GTAAGT consensus sequence had been isolated previously, Vidaud et
  al. (1989) studied the role of this nucleotide in cell-free extracts.
  They found that correct splicing was 98% inhibited. Thus, the last
  residue of exon 1 plays a role at least equivalent to that of the intron
  residue at position 5.
  This hemoglobin variant has a low oxygen affinity, resulting in
  cyanosis. See Reissmann et al. (1961) and Bonaventura and Riggs (1968).
  See Reed et al. (1968).
  See Delanoe-Garin et al. (1985).
  See Clegg et al. (1969).
  See Arous et al. (1982), Rouabhi et al. (1983), Galacteros et al.
  (1984), Elwan et al. (1987), and Kutlar et al. (1989). Hemoglobin
  Knossos is a cause of beta-thalassemia, as is hemoglobin E. Orkin et al.
  (1984) isolated the beta(Knossos) gene and examined its expression in
  HeLa cells. Using a cryptic splice sequence that is enhanced by the
  Knossos substitution, they found that some beta(Knossos) transcripts
  were abnormally processed. In addition to Hb E, a silent substitution at
  beta 24 causes thalassemia by abnormal RNA processing.
  See Harano et al. (1986).
  See Shibata et al. (1961), Pribilla (1962), Hutchison et al. (1964),
  Pribilla et al. (1965), Carrell et al. (1966), Jackson et al. (1967),
  Jones et al. (1967), Woodson et al. (1970), Miller et al. (1971),
  Lie-Injo et al. (1972), and Ohba et al. (1973). Bradley et al. (1980)
  described a convincing instance of gonadal mosaicism accounting for an
  unusual pedigree pattern in a family with Hb Koln. Normal parents had 2
  affected children and each of these 2 children had an affected child.
  This is the most common form of unstable hemoglobin. Horst et al. (1986)
  prepared DNA of 19 nucleotides, corresponding in length to the normal
  and mutant gene sequences, and demonstrated its use for the direct assay
  of the beta-Koln gene. The use of synthetic oligonucleotides established
  that the Hb Koln mutation is due to a G-to-A transition.
  Landin et al. (1994) found Hb Koln as a new mutation in 3 independent
  cases of chronic hemolytic anemia in Sweden. The 2 children and 1 adult
  had partially compensated hemolysis and presented with aggravated
  hemolysis during acute infections in childhood. In 1 patient, acute B19
  parvovirus infection induced an aplastic crisis. Diagnosis was based on
  hemoglobin instability testing and isoelectric focusing of hemoglobin
  dimers. Landin et al. (1994) demonstrated that PCR-RFLP can be used in
  Chang et al. (1998) reported the first case of Hb Koln in the Chinese
  HBB, 15-BP INS
  See Kawata et al. (1988). Whereas 5 amino acid residues are deleted in
  Hb Gun Hill (141900.0095), 5 amino acid residues are inserted at the
  corresponding site in Hb Koriyama.
  Since this same substitution is present with the sickle hemoglobin
  change as one of the two defects in hemoglobin C(Harlem), Konotey-Ahulu
  et al. (1968) suggested that the latter hemoglobin may have arisen by
  intracistronic crossing-over in an individual with the Korle-Bu gene on
  one chromosome and the sickle gene on the other. See Konotey-Ahulu et
  al. (1968) and Honig et al. (1983). Nagel et al. (1993) showed that
  compound heterozygosity for hemoglobin Korle-Bu (Hb KB) and Hb C
  (141900.0038) is associated with moderate chronic hemolytic anemia with
  microcytosis. They found that in vitro hemoglobin crystals formed within
  2 minutes compared with 30 minutes for a mixture of 40% Hb C and 60% Hb
  S and within 180 minutes for 40% Hb C with 60% Hb A. The crystals were
  cubic in contrast with the tetragonal crystals observed in CC and SC
  disease. They concluded that the hemolysis observed in the Hb KB/C
  compound heterozygote is likely to be secondary to the acceleration of
  Hb crystallization.
  See Merault et al. (1986).
  See Malcorra-Azpiazu et al. (1988).
  See De Jong et al. (1968), Juricic et al. (1983), and Schroeder et al.
  HBD137 DEL
  See Honig et al. (1978). A beta-delta (anti-Lepore) variant found in a
  Mexican family, its amino acid structure of the non-alpha polypeptide
  indicated a crossover between amino acids 22 and 50. Honig et al. (1978)
  postulated a series of intergenic crossovers. The residue corresponding
  to the 137th in the delta chain is deleted. See Hb P(Nilotic).
  See Jeppsson et al. (1984) and Ali et al. (1988). This variant was
  detected by oxygen equilibrium measurements and confirmed by IEF in
  Finns with erythrocytosis (Berlin et al., 1987) and in Americans of
  Finnish extraction (Jones et al., 1986). Wada et al. (1987) stated that
  'in Finland, there are many patients with benign familial
  erythrocytosis, some of whom have Hb Helsinki' (q.v.).
  See Bromberg et al. (1973) and Francina et al. (1987). Heterozygotes
  have marked erythrocytosis as in the case of Hb Chesapeake, J
  (Capetown), Malmo, Rainier, Bethesda, Yakima, Kempsey, and Hiroshima.
  This hemoglobin shows decreased stability on warming to 65 degrees C and
  an increased tendency to dissociate in the presence of sulfhydryl
  group-blocking agents. Clinically, it results in mild hemolytic anemia.
  See Keeling et al. (1971), Bratu et al. (1971), and Villegas et al.
  See Schmidt et al. (1977) and Shimizu et al. (1988). Hb Lufkin is
  unstable, causing a mild but well-compensated hemolytic anemia. It was
  initially described in a black American boy from Texas. Gu et al. (1995)
  found this variant in combination with Hb S in a black child who had a
  mild form of sickle cell disease, comparable to SC or SE disease.
  Deletion of beta 17-18 (lys-val). See Solal et al. (1974).
  See Gerald and Efron (1961), Hayashi et al. (1969), Perutz et al.
  (1972), and Horst et al. (1983). This is now usually called simply Hb M
  (Milwaukee) since Hb M (Milwaukee-2) has been shown to be the same as Hb
  M (Hyde Park). The family reported by Pisciotta et al. (1959) was of
  Italian extraction. Hb M (Milwaukee) was also described in a German
  family by Kohne et al. (1977). Oehme et al. (1983) followed the mutant
  beta-globin gene through 3 generations of this family by direct SstI
  analysis at the gene level. The molecular defect is a transversion T to
  A and because of the known recognition sequence of SstI, the nucleotide
  sequence corresponding to amino acids 67 and 68 can be established to be
  GAGCTC instead of GTGCTC.
  See Pisciotta et al. (1959), Heller et al. (1966), Shibata et al.
  (1968), and Stamatoyannopoulos et al. (1976). Rotoli et al. (1992)
  described the case of a cyanotic 7-year-old girl who was found to have
  16% methemoglobin. By molecular genetic studies, they demonstrated that
  this was a case of Hb M (Hyde Park). Hutt et al. (1998) showed by DNA
  sequence analysis that the mutation in M (Milwaukee-2), M (Hyde Park),
  and M (Akita) are all due to a change of codon 92 from CAC (his) to TAC
  This was the abnormal hemoglobin in the family with autosomal dominant
  cyanosis reported by Baltzan and Sugarman (1950). See Horlein and Weber
  (1948), Heck and Wolf (1958), Gerald and George (1959), Gerald and Efron
  (1961), Shibata et al. (1961, 1965), Heller (1962), Josephson et al.
  (1962), Hanada et al. (1964), Murawski et al. (1965), Hobolth (1965),
  Betke et al. (1966), Efremov et al. (1974), Kohne et al. (1975), and
  Baine et al. (1980). Suryantoro et al. (1995) described the his63-to-tyr
  mutation in an Indonesian boy with methemoglobinemia and mild hemolysis.
  The mutation was inherited from the mother. The report further
  demonstrated the worldwide distribution of Hb M-Saskatoon.
  See Harano et al. (1982).
  The hemoglobin Madrid variant was first discovered by Outeirino et al.
  (1974) in a Spanish patient whose parents did not carry the abnormality.
  A second case was observed in an American black teenager by Molchanova
  et al. (1993); although there was a family history of chronic hemolytic
  anemia, none of the family members was available for evaluation. Kim et
  al. (2000) described Hb Madrid in a Korean family with chronic hemolytic
  anemia. The amino acid substitution was due to a change at codon 115
  from GCC (ala) to CCC (pro).
  Yang et al. (1989) found an A-to-G change in codon 19 resulting in
  beta-plus-thalassemia in a Malaysian.
  See Lorkin and Lehmann (1970), Fairbanks et al. (1971), Boyer et al.
  (1972), Berglund (1972), and Berglund and Linell (1972).
  Landin et al. (1996) found this hemoglobin variant with increased oxygen
  affinity causing erythrocytosis in 2 apparently unrelated Swedish
  families. In 1 family, the his97-to-gln substitution was caused by a
  change from CAC-to-CAA; in the other family a CAC-to-CAG change was
  See Marinucci et al. (1983).
  In this abnormal hemoglobin, found by isoelectric focusing in a
  hematologically normal though diabetic Maltese woman living in
  Marseille, Blouquit et al. (1984, 1985) demonstrated a double
  abnormality: a methionyl residue extending the NH2 terminus. This is an
  example of the increasing number of hemoglobin variants detected in the
  course of Hb A1c evaluation in diabetics. Without DNA data, the authors
  concluded that proline in position 2 constitutes a steric impairment to
  the methionyl peptidase that normally eliminates the initiating
  methionine. The same hypothesis has been invoked to explain the apparent
  persistence of the initiator methionyl residue in naturally occurring
  proteins with a met-X sequence at the NH2-terminus, X being either a
  charged amino acid or a proline. Initial sequence, with abnormal
  residues in parentheses, equals H2N-(met)-val-(pro)-leu-thr-glu-glu-.
  Prchal et al. (1986) showed that the only lesion in DNA is an
  adenine-to-cytosine transversion in the second codon. Also see Barwick
  et al. (1985). Boi et al. (1989) detected this variant in Australia in
  the course of monitoring glycated hemoglobin (Hb A1c) in diabetics. It
  causes a discrepancy between the Hb A1c measurement and the clinical
  state of the diabetic patient.
  See Ohba et al. (1989).
  Sciarratta and Ivaldi (1990) discovered this electrophoretically
  slow-moving variant in an Italian family. Numerous red cells contained
  inclusion bodies, and heat and isopropanol tests demonstrated decreased
  stability of the hemoglobin.
  See Buckett et al. (1974).
  The beta chain is only 144 amino acids long. The codon for beta 145 tyr
  has been changed to a terminator. Polycythemia is the clinical
  manifestation. See Winslow et al. (1975) and Rahbar et al. (1983).
  See Hedlund et al. (1984).
  See Adams et al. (1985). Hemoglobin Mississippi has anomalous properties
  that include disulfide linkages with normal beta-, delta-, gamma-, and
  alpha-chains, and the formation of high molecular weight multimers.
  Heterozygotes for Hb MS are clinically and hematologically normal and
  heterozygotes for the beta-plus-thalassemia gene have mild microcytic
  anemia; however, the proband in the family initially discovered by
  Steinberg et al. (1987) had all the hematologic features of thalassemia
  intermedia in the compound heterozygous state. Steinberg et al. (1987)
  suggested that the unexpectedly severe clinical expression in the mixed
  heterozygote, as they called the state, may result from the proteolytic
  digestion of Hb MS as well as the excessive alpha-chains characteristic
  of beta-plus-thalassemia.
  See Harano et al. (1985).
  This is a beta-delta fusion variant, the complement of hemoglobin
  Lepore. For explanation, see hemoglobin P (Congo) (141900.0214). From a
  DNA sequence analysis of the Hb Miyada gene, Kimura et al. (1984)
  concluded that the shift from the 5-prime beta-globin gene to the
  3-prime delta-globin gene occurred somewhere in a homologous sequence
  region between the third nucleotide of codon 17 and the second
  nucleotide of codon 21 of these 2 genes.
  See Nakatsuji et al. (1981) and Ohba et al. (1984).
  See Ohba et al. (1977). Keeling et al. (1991) observed this variant in a
  Caucasian boy from Kentucky.
  As noted by Harthoorn-Lasthuizen et al. (1995), Hb Mizuho is one of the
  more markedly unstable hemoglobin variants and is difficult to detect
  both by protein analysis and by sequencing of the amplified beta chain.
  The instability is due to the introduction of a proline residue in helix
  E, of which 5 residues form part of the heme contact.
  Harthoorn-Lasthuizen et al. (1995) identified a fourth case in a Dutch
  See Shibata et al. (1980).
  See Schneider et al. (1975) and Converse et al. (1985).
  See Ohba et al. (1989).
  See Idelson et al. (1974).
  See Spivak et al. (1982).
  Fast hemoglobin. See Ager and Lehmann (1958), Chernoff and Weichselbaum
  (1958), and Gammack et al. (1961).
  See Clegg et al. (1965), Dobbs et al. (1966), Gottlieb et al. (1967),
  Ballas and Park (1985), and Anderson Fernandes (1989). In heterozygotes
  the concentration of Hb N (Baltimore) is the same as that of Hb A.
  Hemoglobin Kenwood was previously reported incorrectly as having either
  aspartic acid or glutamic acid at beta 143. See personal communication
  from Heller in Hamilton et al. (1969).
  See Schroeder and Jones (1965).
  See Jones et al. (1968).
  See Lena-Russo et al. (1989).
  See Maekawa et al. (1970). Nakamura et al. (1997) identified a second
  case in a Japanese family. The proband was a 47-year-old diabetic male.
  The anomaly was identified during the HPLC assay for HBA1c. The abnormal
  beta chain comprised about 44% of the total beta chain as opposed to 30%
  in the previous report.
  Hb Nagoya is an unstable hemoglobin found in father and son in Japan
  (Ohba et al., 1985).
  During an investigation for erythrocytosis, Keclard et al. (1990) found
  this electrophoretically silent beta chain variant in a French-Caucasian
  male. The sister, mother, and grandmother carried the same abnormal
  hemoglobin in heterozygous state. The mother showed mild erythrocytosis.
  See Moo-Penn et al. (1985).
  This variant was found in a Chinese-American family. See Ranney et al.
  (1967), Kendall and Pang (1980), Saenz et al. (1980), and Todd et al.
  See Finney et al. (1975).
  Deletion of phenylalanine, glutamic acid and serine at either beta 42-44
  or beta 43-45. See Praxedes et al. (1972).
  Increased oxygen affinity. Discovered in a 52-year-old man treated since
  age 20 years for polycythemia vera with various measures including
  several courses of 32(P) (Rahbar et al., 1985).
  See Arends et al. (1977), Brennan et al. (1977), Adams et al. (1982),
  and Gurney et al. (1987).
  See Gordon-Smith et al. (1973) and Orringer et al. (1978). The patient
  of Orringer et al. (1978) was a 7-year-old boy with severe hemolytic
  anemia in whom great improvement in clinical status, including rate of
  growth, was noted 1 year after he underwent a splenectomy and
  cholecystectomy. Cepreganova et al. (1992) described severe hemolytic
  anemia in a 7-year-old Canadian boy with Hb Nottingham. Brabec et al.
  (1994) reported a fourth case in an 8-year-old girl in the Czech
  Republic with severe hemolytic anemia.
  This hemoglobin has been found in American blacks, Bulgarians, and Arabs
  (Kamel et al., 1967). Little et al. (1980) illustrated the fact that
  point mutation can be recognized by the change in susceptibility to
  cleavage by specific restriction endonucleases. The examples were: Hb
  O(Arab) with EcoRI, Hb J(Broussais) with HindIII, and Hb F(Hull) with
  EcoRI. The sickle cell mutation eliminates a site for MnlI. See Ramot et
  al. (1960), Kamel et al. (1966), Vella et al. (1966), Milner et al.
  (1970), and Charache et al. (1977).
  See Beresford et al. (1972).
  High oxygen affinity leads to erythrocytosis. See Moo-Penn et al.
  See Charache et al. (1973).
  See Harano et al. (1983).
  See Harano et al. (1984).
  See Fairbanks et al. (1969) and Lorkin and Lehmann (1970). Thuret et al.
  (1996) described a second case of this unstable hemoglobin. The clinical
  course of a 12-year-old boy was characterized by severe hemolytic anemia
  leading to splenectomy and cholecystectomy at the age of 3.5 years.
  Priapism occurred 8 years after splenectomy, during a hemolytic febrile
  episode, and required aspiration of the corpora cavernosa. Splenectomy
  in cases of chronic hemolytic anemia due to an unstable hemoglobin
  lowers the frequency and severity of acute hemolytic attacks but
  vascular complications often occur. The original patient with Hb
  Olmsted, described by Fairbanks et al. (1969) died of chronic pulmonary
  disease with pulmonary hypertension at age 36 years. The patient
  reported by Thuret et al. (1996) had a French mother and Spanish father.
  This beta-chain variant, associated with erythrocytosis, was first
  discovered in a member of a Czechoslovakian family (Indrak et al.,
  1987). Tagawa et al. (1992) found the same mutation in a Japanese
  Since GUG to AUG is the only single base change that can result in this
  substitution, the codon for beta 20 can be uniquely identified as GUG.
  See Stamatoyannopoulos et al. (1973) and Weaver et al. (1984). Berlin
  and Wranne (1989) described hemoglobin Olympia in a Swedish family.
  Compensatory erythrocytosis results from its high oxygen affinity. See
  Charache et al. (1975), Gacon et al. (1975), Kleckner et al. (1975), and
  Butler et al. (1982).
  Kattamis et al. (1997) found hemoglobin Osler in 2 members of an African
  American family with erythrocytosis. Sequence analysis of DNA from the
  proband showed heterozygosity for a T-to-A transversion at the first
  position of codon 145 in the HBB gene, which resulted in the
  substitution of an asparagine for normal tyrosine. The second cycle of
  C-terminal amino acid sequence analysis of a mixture of alpha- and
  beta-globin chains showed tyrosine, aspartic acid, and small amounts of
  asparagine. Collectively, these results were interpreted as indicating
  the existence of a mutation at codon 145 of the HBB gene, which codes
  for asparagine instead of tyrosine, and that asparagine then undergoes
  initial posttranslational deamidation to aspartic acid. Thus the
  mutation is tyr145asn, not tyr145asp, as initially thought.
  Posttranslational modifications had been described in 4 other
  beta-globin chains and 2 alpha-globin chain variants: Hb Providence
  (141900.0227), Hb Redondo, or Isehara (141900.0404), Hb La Roche-sur-Yon
  (141900.0482), Hb J (Singapore) (141800.0075), Hb Wayne (141850.0004),
  and the only variant in which the posttranslational modification does
  not involve an asn-to-asp substitution, Hb Bristol (val167met-asp;
  Konotey-Ahulu et al. (1971) first observed this nonpathologic mutant in
  a Ghanaian patient with Hb S (141900.0243). By molecular analysis of the
  HBB gene, Giordano et al. (1999) identified the same mutant in 2
  unrelated families of African origin living in the Netherlands, one from
  Ghana and the other from the Dominican Republic. In all carriers of both
  families, the mutation was associated with haplotype 11, an infrequent
  haplotype in the West African population, suggesting a single common
  mutation event. Giordano et al. (1999) stated that because Hb
  Osu-Christiansborg migrates at a similar rate to that of Hb S in
  alkaline hemoglobin electrophoresis, it can easily be mistaken for Hb S.
  Hb Osu-Christiansborg has been described in several parts of the world
  and the mutation is believed to have had independent origins in these
  cases. Rodrigues de Souza et al. (2004) reported the first case of Hb
  Osu-Christiansborg in Brazil. The patient was a healthy 10-year-old boy,
  descendant of Spanish and Brazilian Native Indians. Hematologic data
  were all normal. The mutation was not found in the parents. Paternity
  testing confirmed the biologic relationship between the parents and the
  child, demonstrating that this was a de novo mutation.
  See Silvestroni et al. (1963), Schneider et al. (1969), and Di Iorio et
  al. (1975).
  This is a beta-delta fusion variant, the complement of hemoglobin
  Lepore. Unlike the delta-beta fusion product of Lepore hemoglobin, the
  non-alpha chain resembles beta at the NH2-end. Furthermore, Hb A2 is
  present in normal concentrations and both Hb A and Hb S (or other beta
  variant) can be present in the patient heterozygous for hemoglobin P
  (Congo). The explanation for the origin of hemoglobin Lepore and
  hemoglobin P (Congo) (nonhomologous pairing and unequal crossing-over)
  is diagrammed in Fig. 2.20 (p. 41) of McKusick (1969). The fusion occurs
  between beta 22 and delta 116 (Lehmann and Charlesworth, 1970). See
  Dherte et al. (1959), Lehmann et al. (1964), Lambotte-Legrand et al.
  (1960), and Gammack et al. (1961).
  This is a beta-delta fusion product like Hb P (Congo) and Hb Miyada. The
  fusion site is beta 22 to delta 50. Thus, Hb P(Nilotic) is identical to
  Hb Lincoln Park (141900.0157) except for deletion of delta residue 137
  in Hb Lincoln Park. Thus, it is the complement of Hb Lepore (Hollandia).
  See Badr et al. (1973). Among 8 chromosomes carrying the Hb P (Nilotic)
  hybrid gene, Lanclos et al. (1987) found only 1 haplotype.
  See Brennan et al. (1982).
  See Johnson et al. (1980) and Rahbar et al. (1988).
  This is an unstable hemoglobin resulting in hemolytic anemia. See
  Jackson et al. (1973), Honig et al. (1973), Rousseaux et al. (1980), and
  Shibata et al. (1980).
  See King et al. (1972).
  Nakanishi et al. (1998) provided the second report of Hb Peterborough
  and the first of its occurrence in Japan.
  An unstable hemoglobin leading to hemolytic anemia. No electrophoretic
  abnormality. See Rieder et al. (1969) and Asakura et al. (1981).
  See Baklouti et al. (1988).
  Associated with erythrocytosis. See Blouquit et al. (1980).
  See Lacombe et al. (1985).
  This hemoglobin has an extra reactive thiol group because of the
  substitution of cysteine for serine. Octamers and dodecamers form in
  hemolysates of heterozygotes and homozygotes, respectively, on standing,
  through linkage between tetramers by disulfide bridges. See Tondo et al.
  (1963), Bonaventura and Riggs (1967), Seid-Akhavan et al. (1973), and
  Tondo (1977).
  Salzano (2000) tabulated the Hbb variants observed in Latin America and
  provided further information on Hb Porto Alegre, which had been
  discovered by his group in a family of Portuguese descent living in the
  Brazilian city of that name. Substitution of cysteine for serine at the
  ninth residue of the chain created a sulfhydryl group on the surface of
  the molecule, allowing formation of intermolecular disulfide bonds.
  However, polymerization occurs in vitro but not in vivo, and the variant
  hemoglobin leads to no clinical problems. Lack of polymerization in vivo
  may be because of a compensatory synthesis of glutathione reductase.
  See Charache et al. (1978) and Lacombe et al. (1987).
  See Moo-Penn et al. (1978), Horst et al. (1983), and Villegas et al.
  (1986). Using PCR and direct sequencing, Schnee et al. (1990)
  demonstrated that the molecular defect is a C-to-G substitution in codon
  108; this eliminates an MaeII restriction site.
  The beta variant lys108 enhances the stability of hemoglobin in the
  deoxy-state, conferring low affinity for oxygen binding in vitro. Suzuki
  et al. (2002) generated mutant mice carrying the Presbyterian mutation
  at the beta-globin locus by a targeted knockin strategy. Heterozygous
  mice showed the expression of Hb Presbyterian in 27.7% of total
  peripheral blood without any hematologic abnormalities, which well
  mimicked human cases. On the other hand, homozygous mice exclusively
  expressed Hb Presbyterian in 100% of peripheral blood associated with
  hemolytic anemia, Heinz body formation, and splenomegaly. Hb
  Presbyterian showed instability in an in vitro precipitation assay.
  Erythrocytes from homozygous mice showed a shortened life span when
  transfused into wildtype mice, confirming that the knocked-in mutation
  of lys108 caused hemolysis in homozygous mice. Suzuki et al. (2002)
  stated that this was the first report on the hemolytic anemia of
  unstable hemoglobin in an animal model. The results confirmed the notion
  that the higher ratio of an unstable variant beta-globin chain in
  erythrocytes triggers the pathologic precipitation and induces hemolysis
  in abnormal hemoglobinopathies.
  See Moo-Penn et al. (1976), Charache et al. (1977), and Bardakdjian et
  al. (1985).
  See Tatsis et al. (1972) and Yamada et al. (1977). Schiliro et al.
  (1991) found this hemoglobin variant in a mother and son in Sicily who
  were both clinically and hematologically normal.
  See Pong et al. (1983).
  Cause of polycythemia. See Weatherall et al. (1977).
  See Lorkin et al. (1975) and Sugihara et al. (1985). Beta 82 is at the
  binding site of 2,3-diphosphoglycerate. Hb Rahere is accompanied by
  See Stamatoyannopoulos et al. (1968), Adamson et al. (1969),
  Stamatoyannopoulos and Yoshida (1969), Greer and Perutz (1971), Hayashi
  et al. (1971), and Salhany (1972). Hb Rainier causes erythrocytosis and
  is the only adult hemoglobin that is alkali-resistant. See Hb Bethesda
  (141900.0022), with which Rainier was confused earlier. Peters et al.
  (1985) studied a hemoglobin mutation induced by ethylnitrosourea in the
  mouse. Substitution of cysteine for tyrosine at codon 145 of the HBB
  gene was demonstrated by amino acid analysis. They proposed that an
  A-to-G transition in the tyrosine codon (TAC-to-TGC) had occurred. The
  mouse was polycythemic.
  Carbone et al. (1999) identified a high oxygen affinity hemoglobin
  variant in a 53-year-old male from Naples, Italy, who suffered from
  pulmonary thromboembolism and polycythemia. Characterization of this
  variant at the protein level detected the presence of Hb Rainier. The
  mutation resulted from an A-to-G transition at the second position of
  codon 145 of the HBB gene, resulting in a tyr145-to-cys substitution.
  Substitution of acetylalanine for valine at beta 1. See Moo-Penn et al.
  See Gilbert et al. (1988).
  See Devaraj et al. (1985). Bisse et al. (1991) reported the second
  affected family. The hemoglobin variant was associated with high oxygen
  affinity and erythrocytosis.
  See Efremov et al. (1969) and Winslow and Charache (1975).
  See Moo-Penn et al. (1983).
  See Ranney et al. (1968).
  See Budge et al. (1977), El-Hazmi and Lehmann (1977), Miyaji et al.
  (1977), and Pinkerton et al. (1979).
  See Merault et al. (1985).
  See Gacon et al. (1977) and Danish et al. (1982). Kavanaugh et al.
  (1992) reported x-ray crystallographic studies.
  See Adams et al. (1974).
  The change from glutamic acid to valine in sickle hemoglobin was
  reported by Ingram (1959). Ingram (1956) had reported that the
  difference between hemoglobin A and hemoglobin S lies in a single
  tryptic peptide. His analysis of this peptide, peptide 4, was possible
  by the methods developed by Sanger for determining the structure of
  insulin and Edman's stepwise degradation of peptides.
  Kan and Dozy (1978) used the HpaI restriction endonuclease polymorphism
  (actually the linkage principle) to make the prenatal diagnosis of
  sickle cell anemia (603903). As described in 143020, when 'normal' DNA
  is digested with HpaI, the beta-globin gene is contained in a fragment
  7.6 kilobases long. In persons of African extraction 2 variants were
  detected, 7.0 kb and 13.0 kb long. These variants resulted from
  alteration in the normal HpaI recognition site 5000 nucleotides to the
  3-prime side of the beta-globin gene. The 7.6 and 7.0 kb fragments were
  present in persons with Hb A, while 87% of persons with Hb S had the
  13.0 kb variant. The method is sufficiently sensitive that the cells in
  15 ml of uncultured amniotic fluid sufficed. Restriction enzyme studies
  indicate that whereas Hb S and Hb C originated against the same genetic
  background (as independent mutations) and the Hb S in the Mediterranean
  littoral probably is the same mutation as the West African Hb S, Hb S in
  Asia is apparently a separate mutation. It does not show association
  with the noncoding polymorphism (Kan and Dozy, 1979).
  Mears et al. (1981) used the linkage of the sickle gene with restriction
  polymorphisms to trace the origin of the sickle gene in Africa. They
  found evidence that 2 different chromosomes bearing sickle genes were
  subjected to selection and expansion in 2 physically close but
  ethnically separate regions of West Africa, with subsequent diffusion to
  other areas of Africa. The restriction enzyme MnlI recognizes the
  sequence G-A-G-G, which also is eliminated by the sickle mutation. The
  MstII enzyme recognizes the sequence C-C-T-N-A-G-G. Predictably, the
  resulting fragments are larger than those produced by some other
  enzymes, and MstII is, therefore, particularly useful in prenatal
  diagnosis (Wilson et al., 1982). The sickle cell mutation can be
  identified directly in DNA by use of either of 2 restriction
  endonucleases--DdeI or MstII (Geever et al., 1981; Kazazian, 1982). The
  nucleotide substitution alters a specific cleavage site recognized by
  each of these 2 enzymes. The fifth, sixth, and seventh codons of Hb A
  are CCT-GAG-GAG; in Hb S, they are CCT-GTG-GAG. The recognition site for
  DdeI is C-T-N-A-G, in which N = any nucleoside. Chang and Kan (1982) and
  Orkin et al. (1982) found that the assay using the restriction enzyme
  MstII is sufficiently sensitive that it can be applied to uncultured
  amniotic fluid cells. The enzyme DdeI requires that the amniotic cells
  be cultured to obtain enough DNA for the assay.
  Antonarakis et al. (1984) applied the Kazazian haplotype method to the
  study of the origin of the sickle mutation in Africans. Among 170 beta-S
  bearing chromosomes, 16 different haplotypes of polymorphic sites were
  found. The 3 most common beta-S haplotypes, accounting for 151 of the
  170, were only rarely seen in chromosomes bearing the beta-A gene in
  these populations (6 out of 47). They suggested the occurrence of up to
  4 independent mutations and/or interallelic gene conversions. By
  haplotype analysis of the beta-globin gene cluster in cases of Hb S in
  different parts of Africa, Pagnier et al. (1984) concluded that the
  sickle mutation arose at least 3 times on separate preexisting
  chromosomal haplotypes. The Hb S gene is closely linked to 3 different
  haplotypes of polymorphic endonuclease restriction sites in the
  beta-like gene cluster: one prevalent in Atlantic West Africa, another
  in central West Africa, and the last in Bantu-speaking Africa
  (equatorial, East, and southern Africa). Nagel et al. (1985) found
  hematologic differences between the first 2 types explicable probably by
  differences in fetal hemoglobin production. Ramsay and Jenkins (1987)
  found that 20 of 23 sickle-associated haplotypes in southern-African
  Bantu-speaking black subjects were the same as those found commonly in
  the Central African Republic, a finding providing the first convincing
  biologic evidence for the common ancestry of geographically widely
  separated speakers of languages belonging to the Bantu family. The 3
  haplotypes seen with the beta-S gene in Africa are referred to as
  Senegal, Benin, and Bantu. The 'Bantu line' extends across the waist of
  Africa; south of the line, Bantu languages are spoken. Based on their
  study, Ramsay and Jenkins (1987) suggested that the sickle cell mutation
  arose only once in the Bantu speakers, presumably in their nuclear area
  of origin, before the Bantu expansion occurred about 2,000 years ago. In
  Yaounde, the capital city of Cameroon, Lapoumeroulie et al. (1992)
  observed a novel RFLP pattern in the study of beta-S chromosomes. This
  chromosome contained an A-gamma-T gene and the RFLP haplotype was
  different from all the other beta(S) chromosomes in both the 5-prime and
  3-prime regions. All the carriers of this specific chromosome belonged
  to the Eton ethnic group and originated from the Sanaga river valley.
  Kulozik et al. (1986) found that the sickle gene in Saudi Arabia and on
  the west and east coasts of India exists in a haplotype not found in
  Africa. They concluded that the data are most consistent with an
  independent Asian origin of the sickle cell mutation. The distribution
  of the Asian beta-S-haplotype corresponded to the reported geographic
  distribution of a mild clinical phenotype of homozygous SS disease.
  Ragusa et al. (1988) found that the beta-S gene in Sicily is in linkage
  disequilibrium with the Benin haplotype, the same haplotype observed
  among sickle cell anemia patients from Central West Africa. In addition,
  this haplotype is either nonexistent or very rare among nonsickling
  Sicilian persons. They concluded that the beta-S gene was introduced
  into Sicily from North Africa and that the gene flow originated in
  Central West Africa, traveling north through historically well-defined
  trans-Saharan commercial routes.
  Zeng et al. (1994) indicated that 5 different haplotypes associated with
  Hb S had been described, 4 in Africa (Bantu, Benin, Senegal, and
  Cameroon) and 1 found in both India and Saudi Arabia (Chebloune et al.,
  1988). There is a correlation between disease severity and haplotype for
  at least the 2 extremes of severity: patients with the Indian/Arabian
  haplotype have the mildest course of disease, while those with the Bantu
  haplotype exhibit the most severe course. Nucleotide -530 is a binding
  site for a protein called BP1 (601911), which may be a repressor of the
  HBB gene. BP1 binds with the highest affinity to the Indian haplotype
  sequence and with the weakest affinity to the Bantu sequence, which
  might explain the differences in clinical course in these different
  population groups. Zeng et al. (1994) demonstrated the same sequence at
  -530 bp in patients with the Arabian haplotype as in Indian sickle cell
  anemia patients. This supports the idea of a common origin of the sickle
  cell mutation in individuals in India and Saudi Arabia.
  Sammarco et al. (1988) presented further strong evidence that the Hb S
  gene in Sicily was brought by North African populations, probably during
  the Muslim invasions.
  Currat et al. (2002) studied the genetic diversity of the beta-globin
  gene cluster in an ethnically well-defined population, the Mandenka from
  eastern Senegal. The absence of recent admixture and amalgamation in
  this population permitted application of population genetics methods to
  investigate the origin of the sickle cell mutation (Flint et al., 1993)
  and to estimate its age. The frequency of the sickle cell mutation in
  the Mandenka was estimated as 11.7%. The mutation was found strictly
  associated with the single Senegal haplotype. Approximately 600 bp of
  the upstream region of the beta-globin gene were sequenced for 94
  chromosomes, showing the presence of 4 transversions, 5 transitions, and
  a composite microsatellite polymorphism. The sequence of 22 chromosomes
  carrying the sickle mutation was also identical to the previously
  defined Senegal haplotype, suggesting that the mutation is very recent.
  Maximum likelihood estimates of the age of the mutation using Monte
  Carlo simulations were 45 to 70 generations (1,350-2,100 years) for
  different demographic scenarios.
  Embury et al. (1987) described a new method for rapid prenatal diagnosis
  of sickle cell anemia by DNA analysis. The first step involved a
  200,000-fold enzymatic amplification of the specific beta-globin DNA
  sequences suspected of carrying the sickle mutation. Next, a short
  radiolabelled synthetic DNA sequence homologous to normal beta-A-globin
  gene sequences is hybridized to the amplified target sequence. The
  hybrid duplexes are then digested sequentially with 2 restriction
  endonucleases. The presence of the beta-A or beta-S gene sequence in the
  amplified target DNA from the patient determines whether the beta-A
  hybridization probe anneals perfectly or with a single nucleotide
  mismatch. This difference affects the restriction enzyme digestion of
  the DNA and the size of the resulting radiolabelled digestion products
  which can be distinguished by electrophoresis followed by
  autoradiography. The method was sufficiently sensitive and rapid that
  same-day prenatal diagnosis using fetal DNA was possible. The same test
  could be applied to the diagnosis of hemoglobin C disease. Hemoglobin C
  (Georgetown) also sickles. See Herrick (1910), Sherman (1940), Neel
  (1949), Pauling et al. (1949), Allison (1954), Ingram (1956, 1957,
  1959), Chang and Kan (1981), and Shalev et al. (1988).
  Barany (1991) described a new assay designed to detect single base
  substitutions using a thermostable enzyme similar to the DNA polymerase
  used in PCR. This enzyme, DNA ligase, specifically links adjacent
  oligonucleotides only when the nucleotides are perfectly base-paired at
  the junction. In the presence of a second set of adjacent
  oligonucleotides, complementary to the first set and the target, the
  oligonucleotide products may be exponentially amplified by thermal
  cycling of the ligation reaction. Because a single base mismatch
  precludes ligation and amplification, it will be easily distinguished.
  Barany (1991) demonstrated the utility of the method in discriminating
  between normal and sickle globin genotypes from 10 microliter blood
  Prezant and Fischel-Ghodsian (1992) described a trapped-oligonucleotide
  nucleotide incorporation (TONI) assay for the screening of a
  mitochondrial polymorphism and also showed that it could distinguish the
  genotypes of hemoglobins A/C, A/A, A/S, and S/S. The method was
  considered particularly useful for diagnosing mutations that do not
  produce alterations detectable by restriction enzyme analysis. It also
  requires only a single oligonucleotide and no electrophoretic separation
  of the allele-specific products. It represents an improved and
  simplified modification of the allele-specific primer extension methods.
  (TONI, the acronym for the method, is also the given name of the first
  Grosveld et al. (1987) identified dominant control region (DCR)
  sequences that flank the human beta-globin locus and direct high-level,
  copy-number-dependent expression of the human beta-globin gene in
  erythroid cells in transgenic mice. By inserting a construct that
  included 2 human alpha genes and the defective human beta-sickle gene,
  all driven by the DCR sequences, Greaves et al. (1990) produced 2 mice
  with relatively high levels of human Hb S in their red cells. Use of
  this as an animal model for the study of this disease was suggested.
  Turhan et al. (2002) presented evidence suggesting that a pathogenetic
  mechanism in sickle cell vasoocclusion may reside in adherent
  leukocytes. Using intravital microscopy in mice expressing human sickle
  hemoglobin, they demonstrated that SS red blood cells bind to adherent
  leukocytes in inflamed venules, producing vasoocclusion of cremasteric
  venules. SS mice deficient in P- and E-selectins, which display
  defective leukocyte recruitment to the vessel wall, were protected from
  vasoocclusion. Thus, drugs targeting SS RBC-leukocyte or
  leukocyte-endothelial interactions might prevent or treat the vascular
  complications of this disease.
  Nitric oxide (NO), essential for maintaining vascular tone, is produced
  from arginine by NO synthase. Plasma arginine levels are low in sickle
  cell anemia, and Romero et al. (2002) reported that the sickle
  transgenic mouse model has low plasma arginine. They supplemented these
  mice with a 4-fold increase in arginine over a period of several months.
  Mean corpuscular hemoglobin concentration decreased and the percent
  high-density red cells was reduced. Romero et al. (2002) concluded that
  the major mechanism by which arginine supplementation reduces red cell
  density in these mice is by inhibiting the Ca(++)-activated K(+)
  In a Jamaican study, Serjeant et al. (1968) described 60 patients with
  homozygous sickle cell disease who were 30 years of age or older, and
  Platt et al. (1994) estimated a median survival of 42 to 48 years.
  Serjeant et al. (2007) stated that the sickle cell clinic at the
  University of West Indies had treated 102 patients (64.7% women) who
  survived beyond their 60th birthday. None of the patients received
  hydroxyurea, and only 2 patients with renal impairment received regular
  transfusions. The ages of the patients ranged from 60.2 to 85.6 years.
  Measurement of fetal hemoglobin levels suggested that higher fetal
  hemoglobin levels probably conferred protection in childhood. The major
  clinical problems emerging with age were renal impairment and decreased
  levels of hemoglobin.
  Kwiatkowski (2005) noted that HbS homozygotes have sickle-cell disease,
  whereas heterozygosity confers a 10-fold increase in protection from
  life-threatening malaria (611162) and lesser protection against mild
  Cholera et al. (2008) found that P. falciparum (Pf)-infected HbA/HbS
  erythrocytes did not bind to microvascular endothelial cells as well as
  Pf-infected HbA/HbA erythrocytes. Reduced binding correlated with
  altered display of the major Pf cytoadherence ligand on erythrocyte
  membranes. Cholera et al. (2008) noted that this protective mechanism
  had features in common with that of HbC (141900.0038), and they
  suggested that weakening of cytoadherence interactions may influence the
  degree of malaria protection in HbA/HbS children.
  Modiano et al. (2008) adopted 2 partially independent haplotypic
  approaches to study the Mossi population in Burkina Faso, where both the
  HbS and HbC alleles are common. They showed that both alleles are
  monophyletic, but that the HbC allele has acquired higher
  recombinatorial and DNA slippage haplotypic variability or linkage
  disequilibrium decay and is likely older than HbS. Modiano et al. (2008)
  inferred that the HbC allele has accumulated mainly through recessive
  rather than a semidominant mechanism of selection.
  Gouagna et al. (2010) used cross-sectional surveys of 3,739 human
  subjects and transmission experiments involving 60 children and over
  6,000 mosquitoes in Burkina Faso, West Africa, to test whether the HBB
  variants HbC and HbS, which are protective against malaria, are
  associated with transmission of the parasite from the human host to the
  Anopheles mosquito vector. They found that HbC and HbS were associated
  with significant 2-fold in vivo (P = 1.0 x 10(-6)) and 4-fold ex vivo (P
  = 7.0 x 10(-5)) increases of parasite transmission from host to vector.
  In addition, mean oocyte densities were particularly high in mosquitoes
  fed from HbS carriers.
  This variant has electrophoretic mobility in standard conditions
  identical to that of Hb S but shows a slightly higher pI than Hb S on
  isoelectric focusing. Heterozygous carriers of this variant hemoglobin
  exhibit sickling disorders. This observation may provide a clue to the
  unexplained clinical sickling disorders in some A/S carriers, in whom
  careful biochemical analyses may reveal other examples of double
  mutations in the beta chain. See Monplaisir et al. (1986). Pagnier et
  al. (1990) introduced the val23-to-ile mutation into beta-globin cDNA by
  site-directed mutagenesis. The beta-globin chain was synthesized using
  an expression vector and hemoglobin tetramers were reconstituted. When
  mixed with equal amounts of hemoglobin S, facilitation of polymerization
  was observed. Pagnier et al. (1990) listed 5 other hemoglobin variants
  which contain both the sickle mutation and a second amino acid
  substitution in the same beta chain.
  Popp et al. (1997) bred 2 homozygous viable Hb S Antilles transgene
  insertions into a strain of mice that produce hemoglobins with a higher
  affinity for oxygen than normal mouse Hb. The rationale was that the
  high oxygen affinity hemoglobin, the lower oxygen affinity of Hb S
  Antilles, and the lower solubility of deoxygenated Hb Antilles than Hb S
  would favor deoxygenation and polymerization of human Hb S Antilles in
  the red cells of the high oxygen affinity mice. The investigators found
  that the mice produced a high and balanced expression of human alpha and
  human beta (S Antilles) globins, that 25 to 35% of their RBCs were
  misshapen in vivo, and that in vitro deoxygenation of their blood
  induced 30 to 50% of the RBCs to form classic elongated sickle cells
  with pointed ends. The mice exhibited reticulocytosis, an elevated white
  blood cell count, and lung and kidney pathology commonly found in sickle
  cell patients, which should make these mice useful for experimental
  studies on possible therapeutic intervention of sickle cell disease.
  Langdown et al. (1989) described a doubly substituted sickling
  hemoglobin with the change of glu-to-val at beta 6 (141900.0243) and
  glu-to-lys at beta 121 (141900.0202). The double substitution resulted
  in a variant with reduced solubility and apparent increase in red cell
  sickling tendency. Hemoglobin S (Oman) combines the classic Hb S
  mutation (glu6 to val), with the Hb O (Arab) mutation (glu121 to lys).
  Nagel et al. (1998) studied a pedigree of heterozygous carriers of Hb S
  (Oman) that segregated into 2 types of patients: those expressing about
  20% Hb S (Oman) and concomitant -alpha/alpha-alpha thalassemia and those
  with about 14% of Hb S (Oman) and concomitant -alpha/-alpha thalassemia.
  The higher expressors of Hb S (Oman) had a sickle cell anemia clinical
  syndrome of moderate intensity, whereas the lower expressors had no
  clinical syndrome and were comparable to the solitary case first
  described in Oman. In addition, the higher expressors exhibited a unique
  form of irreversibly sickled cell reminiscent of a 'yarn and knitting
  needle' shape, in addition to folded and target cells. Purified Hb S
  (Oman) has a C(SAT) (solubility of the deoxy polymer) of 11 g/dL, much
  lower than Hb S alone (17.8 g/dL). Another double mutant, Hb S
  (Antilles) (141900.0244), has a similarly low C(SAT) and much higher
  expression (40 to 50%) in the trait form, but has a phenotype that is
  similar in intensity to the trait form of Hb S (Oman). Nagel et al.
  (1998) concluded that the pathology of heterozygous S (Oman) is the
  product of recipient properties of the classic mutation which are
  enhanced by the second mutation at beta-121. In addition, the syndrome
  is further enhanced by a hemolytic anemia induced by the beta-121
  mutation. They speculated that the hemolytic anemia results from the
  abnormal association of the highly positively charged Hb S (Oman) (3
  charges different from normal hemoglobin) with the RBC membrane.
  To characterize better the clinical and laboratory aspects of Hb S
  (Oman), also called Hb S/O (Arab), Zimmerman et al. (1999) reviewed the
  Duke University Medical Center experience. They identified 13 African
  American children and adults with Hb S/O (Arab), ranging in age from 2.7
  to 62.5 years. All patients had hemolytic anemia with a median
  hemoglobin of 8.7 gm/dL and a median reticulocyte count of 5.8%. The
  peripheral blood smear typically showed sickled erythrocytes, target
  cells, polychromasia, and nucleated red blood cells. All 13 patients had
  had significant clinical sickling events, including acute chest syndrome
  (11), recurrent vasoocclusive painful events (10), dactylitis (7),
  gallstones (5), nephropathy (4), aplastic crises (2), avascular necrosis
  (2), leg ulcers (2), cerebrovascular accident (1), osteomyelitis (1),
  and retinopathy (1). Death had occurred in 4 patients, including 2 from
  pneumococcal sepsis/meningitis at ages 5 and 10 years, 1 of acute chest
  syndrome at age 14 years, and 1 of multiorgan failure at age 35 years.
  Zimmerman et al. (1999) concluded that Hb S/O (Arab) disease is a severe
  sickling hemoglobinopathy with laboratory and clinical manifestations
  similar to those of homozygous sickle cell anemia.
  Gale et al. (1988) described a hemoglobin carrying 2 substitutions, the
  standard substitution of Hb S (beta6 glu-to-val) and the substitution of
  Hb Providence (beta82 lys-to-asx). (There is partial postsynthetic
  deamination of asparagine to aspartic acid.) The double mutation is
  electrophoretically silent; if hemoglobin electrophoresis alone were
  done, the abnormality would be missed.
  See Moo-Penn et al. (1977).
  The hemoglobin is unstable, causing hemolytic anemia in the
  heterozygote. See Schneider et al. (1969) and Bogoevski et al. (1983).
  Hull et al. (1998) reported 2 cases of Hb Sabine, in a mother in whom
  the mutation had apparently arisen de novo and her son. They stated that
  more than 100 unstable hemoglobins causing hemolytic anemia had been
  described. Less than 20% of the unstable hemoglobins that have been
  characterized affect the alpha-globin chain.
  Produces erythrocytosis by alteration of the site of fixation of
  2,3-diphosphoglycerate (Rochette et al., 1984).
  See Ohba et al. (1983).
  See Beuzard et al. (1975) and Milner et al. (1976).
  This hemoglobin is characterized by high oxygen affinity, and
  erythrocytosis is associated. See Anderson (1974), Nute et al. (1974),
  and Harkness et al. (1981). Williamson et al. (1995) observed a
  30-year-old man of West Indian origin who showed compound heterozygosity
  for Hb San Diego and Hb S (141900.0243). He had suffered for about 6
  months from severe colicky abdominal pain in episodes of several hours
  duration. He showed erythrocytosis with a hemoglobin value of 18.8 g/dl.
  The Hb San Diego mutation represented a GTG-to-ATG change. The Hb S
  mutation was inherited from the mother; Williamson et al. (1995)
  suggested that the Hb San Diego mutation occurred de novo on the
  chromosome 11 derived from the father. DNA testing was consistent with
  the assumed paternity. The Hb San Diego mutation occurred at a CpG
  dinucleotide. It was concluded that the abdominal pain was due to
  increased blood viscosity and the symptoms were relieved by venesection.
  See Opfell et al. (1968) and Tanaka et al. (1985).
  See Huisman et al. (1971).
  Probable frameshift mutation resulting from deletion of the second base
  of the triplet coding for beta his 143; CAC becomes CCA (PRO). The last
  part of the beta gene code, 143rd residue on, becomes
  pro-ser-ile-thr-lys-leu-ala-phe-leu-leu-ser-asn-phe-tyr-stop (COOH).
  Thus, the beta chain is 156 amino acids long rather than 146. See
  Delanoe et al. (1984).
  Hemoglobin Seattle was discovered by Stamatoyannopoulos et al. (1969),
  who showed that it is associated with a considerable decrease in oxygen
  affinity with almost normal heme-heme interaction and normal Bohr
  effect. It was their conclusion and that of Huehns et al. (1970) that
  the change was ala76-to-glu. However, studies reported by Kurachi et al.
  (1973) led to the conclusion that Hb Seattle has a substitution of
  alanine by aspartic acid at position 70 of the beta polypeptide. Chow et
  al. (1994) reported a second example of Hb Seattle in a Ukranian family.
  Ogata et al. (1986) and Honig et al. (1990) studied this unstable
  variant, which has low oxygen affinity and an increased susceptibility
  to methemoglobin formation.
  The proband had chronic hemolytic anemia aggravated by oxidated drugs
  and common colds. Her 10-year-old son was also affected. Biosynthesis
  studies indicated a normal rate of synthesis, but relatively fast
  degradation of the mutant beta chain (Zeng et al., 1987).
  See Felice et al. (1978), Carcassi et al. (1980), and Moo-Penn et al.
  (1984). Deletion of glutamine at beta 131 in Hb Leslie was reported by
  Lutcher et al. (1976) and the same deletion was reported in Hb Deaconess
  by Moo-Penn et al. (1975). Later, Moo-Penn et al. (1984) showed that Hb
  Deaconess and Hb Leslie are identical to Hb Shelby. All three have
  substitution of lysine for glutamine at beta 131. Adachi et al. (1993)
  described a compound heterozygote for Hb S and Hb Shelby. Hb Shelby,
  like Hb A, can form hybrids with Hb S which participate in polymer
  formation in vitro. However, Hb S/Hb Shelby hybrids copolymerize with Hb
  S less than Hb A/S hybrids. The mild clinical presentation of the
  patient was attributed to this fact.
  See White et al. (1970) and Sansone et al. (1977).
  See Ryrie et al. (1977).
  Williamson et al. (1994) described a 22-year-old Pakistani male with
  polycythemia associated with homozygosity for this high-affinity
  hemoglobin mutant. Whereas 2 previously reported persons with the mutant
  hemoglobin were heterozygotes and were hematologically normal, the
  homozygous state was associated with compensatory erythrocytosis
  resulting from decreased delivery of oxygen to the tissues. Both parents
  and both sibs were heterozygous for the hemoglobin mutant and were
  hematologically normal. This may have been the first example of a
  beta-globin mutation producing polycythemia in homozygotes, but not in
  In a Japanese family, Kobayashi et al. (1987) and Naritomi et al. (1988)
  described a novel HBB mutation that produced the beta-thalassemia
  phenotype through a posttranslational mechanism. Substitution of proline
  for leucine at position 110 greatly reduced the molecular stability of
  the beta-globin subunit, leading to total destruction of the variant
  globin chains by proteolysis. The mutation could be identified after
  digestion with the restriction enzyme MspI. They named the variant Hb
  Showa-Yakushiji, after the 2 districts where the probands resided. Other
  variant hemoglobins that are very unstable and lead to thalassemia
  include Hb Indianapolis (141900.0117) and Hb Quong Sze (141900.0005).
  In 4 unrelated individuals in India, Edison et al. (2005) found the
  hyper-unstable variant Hb Showa-Yakushiji in compound heterozygosity
  with other mutations producing beta-thalassemia or with Hb E
  (141900.0071). In all 4 patients, the mutation was found on the same
  haplotype, which differed from the Japanese haplotype, indicating its
  independent origin in India.
  This HBB gene variant was discovered in a Thai family by Tuchinda et al.
  (1965) and was subsequently identified in several Chinese by Blackwell
  et al. (1972). Chang et al. (1999) observed the same variant in a
  Taiwanese family. DNA analysis detected a G-to-A transition at the first
  base of codon 7 (GAG to AAG). This mutation creates an MboII site that
  is highly specific for Hb Siriraj.
  Hb Sogn was first described in Norway by Monn et al. (1968). Fairbanks
  et al. (1990) described the first known instances of Hb Sogn outside of
  Norway, in 2 families, both of Norwegian descent. Hb Sogn has been
  described in Norwegian families and in American families from the upper
  midwest where settlement of Scandinavian families was common. Miller et
  al. (1996) described the hemoglobin variant in a family residing in
  Illinois; the proband's maternal grandfather was Norwegian. Codon 14
  showed a CTG (leu)-to-CGG (arg) change. The proband married a person who
  was homozygous for alpha-thalassemia-2. The couple had 2 daughters who
  offered the opportunity of comparing data between Hb Sogn heterozygotes
  with 4 alpha-globin genes and 3 alpha-globin genes. Mild microcytosis
  and hypochromia in the father was due to the presence of alpha-thal-2
  homozygosity and that in the mother to the presence of the mildly
  unstable Hb Sogn. Striking microcytosis and hypochromia in 1 daughter
  could be attributed to the combination of a the alpha-thal-2 trait and
  Hb Sogn heterozygosity.
  See Hyde et al. (1972), Jones et al. (1973), and Koler et al. (1973).
  The initiator methionine residue (METi) is preserved. This variant was
  first discovered in a patient who appeared to have markedly elevated Hb
  A(1c) as estimated by ion exchange chromatography. Glycosylated
  hemoglobin measured by a colorimetric method with thiobarbituric acid
  was normal, however. If it were not for the fact that methionine is 1 of
  the 4 N-terminal amino acids (alanine, glycine, serine, methionine) that
  participate in acetylation, this abnormal amino acid substitution would
  have gone unrecognized. Acetylation of the N-terminal methionine residue
  occurs less easily than in other amino acids; thus, hemoglobin South
  Florida could not be recognized by hemoglobin electrophoresis. In
  contrast, acetylation of alanine in hemoglobin Raleigh is 100% and that
  variant can be recognized by hemoglobin electrophoresis. See Boissel et
  al. (1985) and Shah et al. (1986). Malone et al. (1987) reported a
  family study. The fundamental change is not in the codon for the
  initiator mutation but in the codon for the first residue for the mature
  beta-globin chain, valine, which is converted to methionine. Because the
  initiator methionine is retained, this methionine is substituted for
  valine as residue 2 in the mature chain of Hb South Florida.
  Two amino acids, glycine and leucine, are deleted from beta 74 and 75.
  See Wajcman et al. (1973).
  This is a form of Hb M, differing from other Hb M variants by the fact
  that the substitution is not for the histidine at E7 or F8. Hb M
  (Milwaukee) is another. Severe Heinz body anemia, in addition to
  methemoglobinemia, is associated with Hb St. Louis. The beta heme group
  is permanently in a ferric state. See Cohen-Solal et al. (1974),
  Anderson (1976), Thillet et al. (1976), and Wiedermann et al. (1986).
  This hemoglobin variant has a low oxygen affinity, resulting in
  cyanosis. See Arous et al. (1981). Poyart et al. (1990) found that the
  functional properties of St. Mande are intermediary between those of
  normal Hb A and Hb Kansas (0.0145).
  See Como et al. (1984).
  Hb Strasbourg was first observed in a female from northern Portugal and
  in 1 of her 2 children. Garel et al. (1976) incorrectly thought that the
  valine at position 20 was substituted. See Forget (1977). Bisse et al.
  (1998) provided information on a German family with the same
  abnormality. This was the second observation of this hemoglobin variant.
  The 23-year-old propositus had a hemoglobin level of 19.8 g/dl. The
  variant was shown to have a high oxygen affinity. Codon 23 of the HBB
  gene was changed from GTT (val) to GAT (asp).
  No hematologic abnormality. See Wilkinson et al. (1980) and Cin et al.
  See Ali et al. (1988).
  Like hemoglobins Koln and Genova, this hemoglobin has no electrophoretic
  abnormality but is unstable, forming intracellular precipitates. See
  Carrell et al. (1967) and Casey et al. (1978).
  See Jensen et al. (1975).
  See Barwick et al. (1985). Combines substitutions of Hb E and Hb O
  (Arab): substitution of lysine for glutamic acid at beta 26 and of
  glutamine for glutamic acid at beta 121.
  See Blackwell et al. (1971).
  See Baur and Motulsky (1965), Brimhall et al. (1969), Idelson et al.
  (1974), Deacon-Smith and Lee-Potter (1978), and Harano et al. (1985).
  The usual terminal dipeptide 145-146 of the beta chain is lacking and is
  replaced by 10 residues attached to the C-terminal end. Hemoglobin
  Constant Spring is a termination defect of the alpha chain. See Flatz et
  al. (1971). Characterized on the basis of amino acid analysis, this
  variant was assumed to be due to an insertion of the dinucleotide CA
  into codon 146, CAC-to-CA(CA)C, which abolished the normal stop codon at
  position 147 and caused a frameshift with elongation of the beta chain
  by 11 amino acids. The variant had previously been described in a few
  Thai families. Hoyer et al. (1998) reported the DNA sequence of Hb Tak
  in an individual of Cambodian descent who was a Hb E/Tak compound
  heterozygote. In contrast with extended variants of the alpha-globin
  gene that are expressed as alpha-thalassemias, the hematologic effect of
  Hb Tak/Hb E was a mild polycythemia. The combination of Hb Tak/Hb E was
  not expressed as a thalassemia.
  Shih et al. (2005) reported heterozygosity for Hb Tak in a Taiwanese
  See Iuchi et al. (1980) and Kawata et al. (1989).
  See Johnson et al. (1980).
  In a healthy 34-year-old Chinese male of Han nationality, Li et al.
  (1990) identified a hemoglobin variant and showed that it had a
  replacement of glutamine by arginine at residue 39.
  This hemoglobin and 3 others with a single amino acid substitution at
  the same site have reduction in affinity for oxygen. See Bernini and
  Giordano (1988).
  Deletion of residues 56-59 of the beta chain. See Shibata et al. (1970).
  See Wajcman et al. (1973).
  See Hirano et al. (1981) and Imai et al. (1981).
  See Kohne et al. (1976). Philippe et al. (1993) described this
  hemoglobin variant, a cause of methemoglobinemia, in a 53-year-old
  Belgian woman. Her father had been cyanotic throughout his life. This
  was the second report of this hemoglobin variant.
  See Mrad et al. (1988).
  See Bursaux et al. (1978).
  See Kendall et al. (1977).
  See Jones et al. (1976).
  See Puett et al. (1977) and Paniker et al. (1978).
  See Adams et al. (1981). When they failed to find evidence of deletion
  of leu75 in genomic DNA, Coleman et al. (1988) proposed somatic
  mutation. A more plausible explanation, perhaps, is one parallel to that
  obtaining in the case of Hb Atlanta-Coventry (141900.0013).
  This mutation was discovered as a silent and asymptomatic variant in an
  87-year-old French woman who coincidentally had polycythemia vera
  (Wajcman et al., 1989).. Carbone et al. (2001) reported the second
  observation of this hemoglobin variant in 3 related subjects from
  Montesarchio in southern Italy. The DNA change was ACC to ATC.
  See Kuis-Reerink et al. (1976), Ockelford et al. (1980), Sciarratta et
  al. (1985), and Falcioni et al. (1988). Blanke et al. (1989) reported a
  possible de novo mutation in a Dane.
  See Wilson et al. (1984).
  See Perutz and Lehmann (1968) and Lorkin et al. (1974).
  See Jones et al. (1976-77), Quarum et al. (1983), and Martinez and
  Canizares (1984).
  Gilbert et al. (1989) found this variant in a 9-month-old child who
  presented with hemolytic anemia in association with intercurrent viral
  infection. Instability of the hemoglobin molecule as well as increase in
  oxygen affinity was demonstrated.
  See Taketa et al. (1975).
  Polycythemia occurs with this hemoglobinopathy as with hemoglobin
  Chesapeake. See Jones et al. (1967), Novy et al. (1967), and Osgood et
  al. (1967).
  See Harano et al. (1990).
  Hemoglobin Yamagata as reported by Harano et al. (1990) was caused by a
  change of codon 132 in the HBB gene from AAA (lys) to AAC (asn). Han et
  al. (1996) found the same amino acid substitution in a 37-year-old
  Korean woman to be caused by a change of codon 132 from AAA to AAT. No
  distinctive clinical abnormalities were detected.
  See Kagimoto et al. (1978).
  See Nakatsuji et al. (1981). Plaseska et al. (1991) described a de novo
  mutation in a Yugoslavian boy with severe transfusion-dependent
  hemolytic anemia. The patients of Nakatsuji et al. (1981) were a
  33-year-old Japanese woman with chronic hemolytic anemia and her son
  with milder symptoms.
  See Bare et al. (1976) and Kosugi et al. (1983).
  Reduced oxygen affinity like hemoglobin Kansas. See Imamura et al.
  Substitution in beta chain results in increased oxygen affinity leading
  to erythremia and abnormal polymerization manifested in heterozygotes by
  hybrid hemoglobin molecules containing both the Ypsi beta chain and the
  normal beta chain. See Glynn et al. (1968) and Rucknagel (1971).
  See Yanase et al. (1968) and Marengo-Rowe et al. (1968).
  See Harano et al. (1981) and Ohba et al. (1990).
  Drug-induced hemolysis results from this variant hemoglobin. The
  affinity of Hb Zurich for carbon monoxide is about 65 times that
  observed in normal hemoglobin A. Carboxyhemoglobin content in persons
  with Hb Zurich varied from 3.9 to 6.7% for nonsmokers and 9.8 to 19.7%
  for smokers. Hemolysis was less in smokers, presumably because of
  stabilization of Hb Zurich by CO. See Huisman et al. (1960), Muller and
  Kingma (1961), Frick et al. (1962), Rieder et al. (1965), Dickerman et
  al. (1973), Zinkham et al. (1979, 1980, 1983), Dlott et al. (1983), and
  Virshup et al. (1983).
  Miranda et al. (1994) identified Hb Zurich in a 38-year-old woman who
  had a hemolytic crisis after administration of an antibiotic for urinary
  tract infection. This hemoglobin variant was first identified by protein
  analysis and then by DNA sequencing.
  Aguinaga et al. (1998) studied 4 members of a Kentucky family whom they
  had identified as Hb Zurich carriers. During pregnancy, the proband
  developed hemolytic anemia with Heinz bodies when treated for a urinary
  tract infection with sulfonamide. Because of severe anemia, the patient
  was transfused several times and ultimately splenectomized. The Kentucky
  family studied in this report was part of a larger kindred that was
  known to contain 19 members who were Hb Zurich carriers.
  Zinkham et al. (1979) demonstrated in vitro thermal denaturation of Hb
  Zurich as a cause of anemia during fever.
  This variant was found in Chinese. Chang et al. (1979) and Chang and Kan
  (1979) presented evidence that beta-zero-thalassemia is a nonsense
  mutation, the first identified in man. By molecular hybridization they
  showed that the beta gene is present. In different patients variable
  amounts of beta-like globin mRNA is present. They sequenced mRNA and
  found that noncoding regions at both ends were normal but at the
  position corresponding to amino acid no. 17, the normal lysine codon AAG
  was converted to UAG, a terminator. Such a nonsense mutation should be
  overcome by means of suppressor tRNA which allows the ribosome to read
  through a terminator codon by inserting an amino acid. In vitro addition
  of a serine suppressor tRNA from yeast resulted in human beta-globin
  synthesis. Cell-free assays with suppressor tRNAs may be useful for
  detecting nonsense mutations in other human genetic disorders. Steger et
  al. (1993) showed that this AAG-to-TAG nonsense mutation and the
  hemoglobin E mutation, common causes of beta(+)-thalassemia and
  beta-zero-thalassemia in Southeast Asia, can be detected using
  allele-specific PCR, known also as the amplification refractory mutation
  system (ARMS).
  Krawczak et al. (2000) pointed out that this was the first single
  basepair substitution in a human gene underlying a genetic disorder to
  be reported. Knowledge of the amino acid substitution responsible for
  sickle hemoglobin permitted imperfect inference of the nucleotide change
  because of redundancy of the code.
  Chehab et al. (1986) found evidence for new mutation in the codon at
  beta-39 from CAG (glutamine) to the stop codon TAG. The beta-39 nonsense
  mutation is the second most common beta-thalassemia lesion in Italy,
  accounting for a third of cases, and the most common in Sardinia,
  accounting for 90% of cases there. In Sardinia, the beta-39 mutation has
  been identified with 9 different haplotypes. All this suggested to
  Chehab et al. (1986) that beta-39 is a mutation hotspot. Trecartin et
  al. (1981) found that the form of beta-zero-thalassemia that is
  predominant in Sardinia is caused by a single nucleotide mutation at the
  position corresponding to amino acid number 39 and converting a
  glutamine codon (CAG) to an amber termination codon (UAG). (Epstein et
  al. (1963) described 'amber' mutants of phage T4 in a frequently cited
  paper in a Cold Spring Harbor Symposium on Quantitative Biology. The
  origin of the unusual name 'amber' is, as Witkowski (1990) called it,
  'an interesting footnote in the history of molecular biology.' Edgar
  (1966) recounted that R. H. Epstein and C. M. Steinberg, then at the
  California Institute of Technology, had promised Harris Bernstein, then
  at Yale University, that the mutants, if any were found, would be named
  after his mother. They were found and were named 'amber,' the English
  equivalent of 'Bernstein.' The other 2 'stop' codons, UGA and UAA, are
  sometimes referred to as 'opal' and 'ochre,' respectively.) Rosatelli et
  al. (1992) used denaturing gradient gel electrophoresis (DGGE) followed
  by direct sequence analysis of amplified DNA to study 3,000
  beta-thalassemia chromosomes in the Sardinian population. They confirmed
  that the predominant mutation, present in 95.7% of beta-thalassemia
  chromosomes, was gln39-to-ter.
  See Kazazian et al. (1984). The mutation that Kazazian et al. (1984)
  demonstrated in Asian beta-thalassemia patients was the result of a
  TGG-to-TAG mutation. Ribeiro et al. (1992) demonstrated the frequent
  occurrence in central Portugal of beta-zero-thalassemia due to a change
  of codon 15 for tryptophan to a stop codon; the basis, however, was a
  TGG-to-TGA mutation.
  See Kazazian et al. (1986), Fei et al. (1989) and Adams et al. (1990).
  Thein et al. (1990) identified the E121X mutation in 3 British families
  with dominantly inherited inclusion body beta-thalassemia (603902). The
  clinical features were that of a dominant dyserythropoietic anemia
  associated with inclusion bodies in normoblasts. The condition was
  described originally by Weatherall et al. (1973) and was previously
  labeled dyserythropoietic, congenital, Irish or Weatherall type. The
  original family reported by Weatherall et al. (1973) was found by Thein
  et al. (1990) to carry an insertion/deletion mutation with frameshift in
  the HBB gene (141900.0520).
  See Boehm et al. (1986).
  Atweh et al. (1988) described a novel nonsense mutation in a Chinese
  patient: a G-to-T substitution at the first position of codon 43, which
  changed the glutamic acid coding triplet (GAG) to a terminator codon
  (TAG). They incorrectly referred to a patient carrying both the beta-17
  and the beta-43 nonsense mutation as being a double heterozygote rather
  than a compound heterozygote.
  See Gonzalez-Redondo et al. (1988).
  See Fucharoen et al. (1989).
  In a person of British extraction, Kazazian et al. (1989) found a
  gln127-to-pro mutation as the basis of a 'dominant' form of
  beta-plus-thalassemia. This form of thalassemia is due to instability of
  the beta-globin chains containing the particular mutation. Kazazian et
  al. (1992) again reported on the CAG-CGG missense mutation at codon 127
  which caused thalassemia intermedia with hemolysis in 3 generations of a
  British-American family. They commented that the paucity of
  high-frequency exon 3 mutations and the worldwide distribution of the
  few that are observed are probably attributable to their phenotypic
  severity and lack of increased genetic fitness in relation to malaria.
  In a Japanese patient with beta-plus-thalassemia, Hattori et al. (1989)
  found deletion of nucleotides AGG from codons 127 and 128 (CAG to GCT)
  resulting in replacement of gln127 and ala128 by proline (CCT).
  In an Italian with beta-plus-thalassemia, Podda et al. (1989, 1991)
  found a val60-to-glu substitution.
  Frameshift, -AA in codon 8, AAG to G, was found in a Turkish patient by
  Orkin and Goff (1981). This mutation was also found in homozygous state
  in DNA from the archeologic remains of a child with severe bone
  pathology consistent with thalassemia (Filon et al., 1995). The remains
  came from a grave thought to date to the Ottoman period, sometime
  between the 16th and 19th centuries. From the tooth development, it was
  estimated that the child died at the age of about 8 years, whereas
  patients with this mutation would be expected to be
  transfusion-dependent from early infancy. Filon et al. (1995) also found
  a rare DNA polymorphism: a C-to-T transition in the second codon of the
  HBB gene that did not alter the corresponding amino acid. This
  polymorphism is found in 13% of present-day Mediterranean
  beta-thalassemia chromosomes and is part of a haplotype (haplotype IV)
  that is associated with relatively high levels of fetal hemoglobin. The
  disease may have run a milder course because of linkage to haplotype IV.
  Frameshift, -C, codon 16, GGC to GG, was found in Asian Indians by
  Kazazian et al. (1984).
  Frameshift, -C, codon 44, TCC to TC, was found in a Kurdish patient by
  Kinniburgh et al. (1982).
  HBB, INS, 1-BP, G, CODONS 8/9
  Frameshift, +G, codons 8/9, AAGTCT to AAGGTCT was found in an Asian
  Indian by Kazazian et al. (1984).
  HBB, 4-BP DEL, 41/42CTTT
  Frameshift, -4, codons 41/42, TTCTTT to TT, was found in an Asian Indian
  by Kazazian et al. (1984) and in Chinese by Kimura et al. (1983).
  Lau et al. (1997) found that the deletion of CTTT at codons 41/42
  accounted for 40% of all beta-thalassemia alleles in Hong Kong. Chiu et
  al. (2002) designed allele-specific primers and a fluorescent probe for
  detection of this mutation in the HBB gene from maternal plasma by
  real-time PCR. Using this method, they showed that beta-thalassemia
  major could be excluded from fetal inheritance by demonstrating absence
  of inheritance of the paternally transmitted mutation. By studying
  circulating fetal DNA in the maternal plasma for this mutation, Chiu et
  al. (2002) added beta-thalassemia to the list of disorders that could be
  prenatally diagnosed using this noninvasive method, which had previously
  demonstrated usefulness in diagnosing sex-linked diseases (Costa et al.,
  2002) and fetal rhesus D status (Lo et al., 1998).
  Frameshift, -A, codon 6, GAG to GG, was found in Mediterranean patients
  by Kazazian et al. (1983). Bouhass et al. (1990) found the same mutation
  in an Algerian patient who was a genetic compound. Rosatelli et al.
  (1992) found that this mutation accounted for 2.1% of mutations carried
  by 3,000 beta-thalassemia chromosomes from the Sardinian population.
  Romey et al. (1993) described an improved procedure that allows the
  detection of single basepair deletions on nondenaturing polyacrylamide
  gels and demonstrated its applicability for identifying this mutation.
  Frameshift, +A, codons 71/72, TTAGT to TTTAAGT, was found in Chinese by
  Cheng et al. (1984).
  Frameshift, +G, codons 106/107, CTGGGC to CTGGGGG, was found in American
  blacks by Wong et al. (1987).
  Frameshift, -C, codon 76, GCT to GT, was found in an Italian by DiMarzo
  et al. (1988). Rosatelli et al. (1992) found that this mutation was
  responsible for 0.7% of the mutations carried by 3,000 beta-thalassemia
  chromosomes in the Sardinian population.
  Frameshift, -G, codon 37, TGG to G, was found in a Kurdish patient by
  Rund et al. (1989, 1991).
  Frameshift, -CT, codon 5, CCT to CC, was found in a Mediterranean
  patient by Kollia et al. (1989).
  Frameshift, -T, codon 11, GTT to GT, was found in a Mexican patient by
  Economou et al. (1990).
  Frameshift, -C, codon 35, TAC to TA, was found in Indonesia by Yang et
  al. (1989).
  Frameshift, -CT, codon 114, CTG to G, was found in a French patient by
  Beris et al. (1988). Hb Geneva is an unstable hemoglobin producing a
  hemolytic anemia with inclusion bodies in the peripheral blood after
  splenectomy. Heterozygotes show manifestations of a thalassemia-like
  Frameshift, +G, codon 14/15, CTGTGG to CTGGTGG, was found in Chinese by
  Chan et al. (1988).
  Frameshift, -7 nucleotides from codons 37-39, TGGACCCAG, was found in a
  Turkish patient by Schnee et al. (1989).
  Frameshift, +TG, codon 94 (GAC), was found in a Mediterranean patient by
  Pirastu et al. (1990).
  Frameshift, -G, codon 64, GGC to GC, was found in a Swiss woman
  heterozygous for beta-thalassemia by Chehab et al. (1989). This was a
  spontaneous mutation as originally described by Tonz et al. (1973). The
  father was 45 years old when the proband was born. By haplotyping,
  Chehab et al. (1989) showed, furthermore, that the mutation had arisen
  on the father's chromosome 11.
  Frameshift, -G, codon 109, GTG to TG, found in a Lithuanian by Kazazian
  et al. (1989).
  Frameshift, -T, codon 36/37, CCTTGG to CCTGG, was found in Iranian Kurds
  by Rund et al. (1989, 1991).
  Frameshift, +C, codons 27/28, GCCCTG to GCCCCTG, was found in Chinese by
  Cai et al. (1989).
  Frameshift, +T, codon 71, TTT to TTTT, was found in Chinese by Kazazian
  This initiator codon mutant, ATG to AGG, was found in Chinese
  individuals by Kazazian (1990).
  This initiator codon mutant, ATG to ACG, was found in Yugoslavians by
  Jankovic et al. (1989). The same mutation was found by Beris et al.
  (1993) in a father and daughter of a family originating from Bern,
  Switzerland. Unlike the first reported family, of Yugoslavian origin,
  the Swiss patients had high Hb F levels. The mutation converted the
  initiator methionine to threonine and abolished an NcoI recognition
  (In the case of many other genes in which the mutations have been
  characterized on the basis of the gene itself, the codon count begins
  with the initiator methionine. In such a system, this mutation would be
  designated met1-to-thr and the hemoglobin S mutation would be designated
  Molchanova et al. (1998) characterized the beta-thalassemia present in 3
  generations of a branch of the family of the Russian poet Mihail
  Yurievich Lermontov. The hematologic data for affected members of 3
  generations were compatible with a beta-thal heterozygosity. Sequence
  analysis showed an ATG-to-ACG change in the initiation codon. The family
  in which it was first observed by Jankovic et al. (1989, 1990) was said
  to have been of Croatian origin. In that family, the mutation was
  accompanied by a CAC-to-CAT change in codon 2 of the same chromosome;
  this common polymorphism was not seen in the Russian family.
  HBB, IVS1, G-A, +1
  Splice junction mutant, G to A, position 1 of IVS1, was found by Orkin
  et al. (1982) in a Mediterranean patient.
  HBB, IVS1, G-T, +1
  Splice junction mutant, G to T, at position 1 of IVS1 was found in an
  Asian Indian and in Chinese by Kazazian et al. (1984).
  HBB, IVS2, G-A, +1
  A splice junction mutant, G to A, at position 1 of IVS2 was found in a
  Mediterranean by Treisman et al. (1982), in a Tunisian by Chibani et al.
  (1988), and in an American black by Thein et al. (1988). The same
  mutation was found by Hattori et al. (1992), who referred to the
  mutation as IVS2-1 (G-A).
  This is one of the earliest mutations at a 5-prime splice site to be
  described. In an analysis of 101 different examples of point mutations
  that lie in the vicinity of mRNA splice junctions and that have been
  held to be responsible for human genetic disease by altering the
  accuracy or efficiency of mRNA splicing, Krawczak et al. (1992) found
  that 62 were located at 5-prime splice sites, 26 at 3-prime splice
  sites, and 13 resulted in the creation of novel splice sites. They
  estimated that up to 15% of all point mutations causing human genetic
  disease result in an mRNA splicing defect. Of the 5-prime splice site
  mutations, 60% involve the invariant GT dinucleotides.
  Sierakowska et al. (1996) found that treatment of mammalian cells stably
  expressing the IVS2-654 beta HBB gene with antisense oligonucleotides
  targeted at the aberrant splice sites restored correct splicing in a
  dose-dependent fashion, generating correct human beta-globin mRNA and
  polypeptide. Both products persisted for up to 72 hours after treatment.
  The oligonucleotides modified splicing by a true antisense mechanism
  without overt unspecific effects on cell growth and splicing of other
  pre-mRNAs. Sierakowska et al. (1996) stated that this novel approach in
  which antisense oligonucleotides are used to restore rather than to
  downregulate the activity of the target gene is applicable to other
  splicing mutants and is of potential clinical interest.
  This mutation is frequent among patients in southern China and Thailand,
  accounting for 20% of beta-thalassemia in some regions. It causes
  aberrant RNA splicing. Lewis et al. (1998) modeled this mutation in
  mice, replacing the 2 (cis) murine adult beta-globin genes with a single
  copy of the human mutant HBB gene. No homozygous mice survived
  postnatally. Heterozygous mice carrying this mutant gene produced
  reduced amounts of mouse beta-globin chains and no human beta globin,
  and had a moderately severe form of beta-thalassemia. Heterozygotes
  showed the same aberrant splicing as their human counterparts and
  provided an animal model for testing therapies that correct splicing
  defects at either the RNA or DNA level.
  HBB, IVS1, T-G, +2
  Splice junction mutant, T to G, at position 2 of IVS1 was found in a
  Tunisian by Chibani et al. (1988).
  HBB, IVS2, T-C, +2
  Splice junction mutant, T to C, at position 2 of IVS1 was found in an
  American black by Gonzalez-Redondo et al. (1989). Of 33 thalassemic
  chromosomes in Algerian patients studied by Bouhass et al. (1990), 7
  carried the T-to-C transition at position 2 in IVS1. Thus, the mutation
  may be common in the Algerian population. They observed 2 patients who
  were homozygous for the substitution and had no detectable Hb A by
  standard electrophoresis procedures. Interestingly, the other 2 possible
  changes at this position have also been observed; see 141900.0349 and
  HBB, IVS1, 17-BP DEL
  Deletion of 17 nucleotides that removed the acceptor splice site from
  IVS1 was found in a Kuwaiti by Kazazian and Boehm (1988).
  HBB, IVS1, 25-BP DEL
  Deletion of 25 nucleotides that removed the acceptor splice site of IVS1
  was found in an Asian Indian by Orkin et al. (1983).
  HBB, IVS2, A-G, -2
  Change from CCACAGC to CCACGGC (A to G at position -2) in the acceptor
  splice site of IVS2 was found in American blacks by Antonarakis et al.
  (1984) and Atweh et al. (1985).
  This is one of the earliest-described examples of mutation in the
  3-prime splice site affecting mRNA splicing. In an analysis of 101
  different examples of point mutations occurring in the vicinity of mRNA
  splice junctions and resulting in human genetic disease, Krawczak et al.
  (1992) found that 26 involved 3-prime splice sites.
  HBB, IVS2, A-C, -2
  Change from CCACAGC to CCACCGC (A to C at position -2) at acceptor
  splice site of IVS2 was found in American blacks by Padanilam and
  Huisman (1986).
  HBB, IVS1, 44-BP, SS DEL
  Deletion of 44 nucleotides that removed the IVS1 donor splice site was
  found in a Mediterranean patient by Kazazian and Boehm (1988).
  HBB, IVS1, G-A, -1
  In an Egyptian child with thalassemia major, Deidda et al. (1990) found
  heterozygosity for a G-to-A substitution at position -1 of IVS1, which
  altered the conserved dinucleotide AG present in the consensus acceptor
  sequence. The other chromosome carried the T-to-C mutation at position 6
  of the first intervening sequence (IVS1) (141900.0360). The latter
  mutation was associated with haplotype 6, frequently observed in
  Mediterranean areas; the new mutation was associated with haplotype 1.
  This gene can be added to the list of mutations that can be identified
  by Southern analysis using AflII.
  HBB, IVS1, G-C, +5
  G-to-C change at position 5 of the donor site consensus sequence of IVS1
  (CAG-GTTGGT to CAG-GTTGCT) was found in an Asian Indian by Kazazian et
  al. (1984) and in a Chinese by Cheng et al. (1984).
  HBB, IVS1, G-T, +5
  G-to-T change at position 5 of the donor site consensus sequence of IVS1
  (CAG-gttggt-to-CAG-gttgtt) was found in a Mediterranean patient and an
  Anglo-Saxon patient by Atweh et al. (1987) and in an American black by
  Gonzalez-Redondo et al. (1988). The 2 cases of Atweh et al. (1987) were
  in different RFLP backgrounds, suggesting that they represented
  independent mutations. Atweh et al. (1987) showed that after transfer of
  the cloned genes into HeLa cells, followed by transient expression,
  partial inactivation of the normal donor splice site of IVS1 and
  activation of 2 major and 1 minor cryptic splice sites occur. The
  effects of this mutation on mRNA splicing were similar to those of
  another beta-thalassemia gene with a G-to-C transition at the same
  position (141900.0357). In a rare case of beta-thalassemia in a German
  family, Eigel et al. (1989) found a G-to-T transversion at the intron 1
  donor site of the beta-globin gene. This may be the same mutation. The
  patient was homozygous for this mutation and had died at age 27 of heart
  failure resulting from iron overload.
  HBB, IVS1, G-A, +5
  G-to-A change at position 5 of the donor site consensus sequence of IVS1
  (CAG-GTTGGT to CAGGTTGAT) was found in an Algerian by Lapoumeroulie et
  al. (1986).
  HBB, IVS1, T-C, +6
  T-to-C change at position 6 of the donor site consensus sequence of IVS1
  (CAG-GTTGGT to CAG-GTTGGC) was found in a Mediterranean patient by Orkin
  et al. (1982).
  HBB, IVS2, C-A, -3
  A C-to-A change at position -3 in the acceptor splice site of IVS2 (CAG
  to AAG) was found in an Iranian, an Egyptian, and an American black by
  Gonzalez-Redondo et al. (1988) and Wong et al. (1989).
  HBB, IVS1, T-G, -3
  A T-to-G change at position -3 in the acceptor splice site of IVS1 (TAG
  to GAG) was found in a Saudi Arabian by Wong et al. (1989). Indeed, Wong
  et al. (1989) identified 2 different nucleotide substitutions in
  consensus acceptor splice sequences of the beta-globin gene leading to
  beta-thalassemia. One was at the IVS1/exon 2 junction and the other at
  the IVS2/exon 3 junction (141900.0361). Both mutations were single
  nucleotide substitutions, T-to-G and C-to-A, at position -3 immediately
  adjacent to the invariant AG dinucleotide. For the IVS2/exon 3 mutation,
  abnormal splicing into the cryptic splice site at IVS2 nucleotide 579
  was demonstrated.
  HBB, IVS1, C-A, -8
  A C-to-A change at position -8 in the acceptor splice site of IVS2 was
  found in an Algerian by Beldjord et al. (1988).
  HBB, IVS1, G-A, +110
  A G-to-A change at position 110 of IVS1 was found in a Mediterranean
  patient by Spritz et al. (1981) and Westaway and Williamson (1981). The
  mutation created a new splice acceptor site. Kaplan et al. (1990)
  studied the molecular basis of beta-thalassemia minor, which has a
  frequency of about 1% among French Canadians residing in Portneuf County
  of Quebec Province. They showed that there were 2 different
  beta-thalassemia mutations segregating in the population: an RNA
  processing mutation involving nucleotide 110 of IVS1 on haplotype 1 and
  a point mutation leading to chain termination through a nonsense codon
  at position 39 (141900.0312), occurring on haplotype 2.
  HBB, IVS1, T-G, +16
  A T-to-G change at position 16 of IVS1 was found in a Mediterranean
  patient by Metherall et al. (1986). The mutation created a new acceptor
  splice site.
  HBB, IVS2, T-G, +705
  A T-to-G change at position 705 of IVS2 was found in a Mediterranean
  patient by Dobkin et al. (1983). The mutation created a new acceptor
  splice site.
  HBB, IVS2, C-G, +745
  A C-to-G change at position 745 of IVS2 was found in a Mediterranean
  patient by Orkin et al. (1982). The mutation created a new acceptor
  splice site.
  HBB, IVS2, C-T, +654
  A C-to-T change at position 654 of IVS2 was found in a Chinese by Cheng
  et al. (1984).
  In an American black, Goldsmith et al. (1983) found a change in codon 24
  from GGT to GGA. Although silent in terms of changing the amino acid
  sequence, the mutation affected processing of mRNA.
  HBB, -101C-T
  Gonzalez-Redondo et al. (1989) found a C-to-T change in nucleotide -101
  in an asymptomatic Turkish carrier of beta-thalassemia. This is one of
  the transcriptional mutants causing beta-thalassemia. Ristaldi et al.
  (1990) showed that this mutation is a relatively frequent cause of
  beta-thalassemia in the Italian population, where it is always
  associated with haplotype 1. Compound heterozygosity for this promoter
  mutation and a mutation for severe beta-thalassemia results in a mild
  form of thalassemia intermedia (Murru et al., 1991). In studies of
  infants of Italian couples, 1 member of which was heterozygous for this
  promoter mutation, Murru et al. (1993) demonstrated that mutation leads
  to a more severe defect in beta-globin chain production in infancy than
  in adulthood. The moment of transition from the fetal-infant to the
  adult pattern of expression seems to be at about 2 years of age. This
  age-related pattern of expression had not been detected for other
  beta-thalassemia mutations. Assuming the existence of different distal
  CACCC box binding proteins with an activating function on the
  beta-globin gene promoter in fetal and adult ages, Murru et al. (1993)
  speculated that the fetal type interacts less efficiently with the
  mutated CACCC promoter as compared with the adult one. They suggested
  that the findings permit one to predict a mild phenotype even when HbA
  is absent in the newborn.
  Maragoudaki et al. (1999) reported the clinical, hematologic,
  biosynthetic, and molecular data on 25 double heterozygote
  beta-thalassemia intermedia patients and 45 beta-thalassemia
  heterozygotes with the C-to-T substitution at nucleotide position -101
  from the cap site, in the distal CACCC box of the HBB promoter. This
  mutation is considered the most common among the silent beta-thalassemia
  mutations in Mediterranean populations. Of the 25 compound heterozygotes
  for the promoter mutation and common severe beta-thalassemia mutations,
  all but 1 had mild thalassemia intermedia preserving hemoglobin levels
  around 9.5 g/dl and hemoglobin F levels less than 25%. Strict assessment
  of hematologic and biosynthetic findings in the heterozygotes for the
  promoter mutation demonstrated that less than half of them had
  completely normal (silent) hematology.
  HBB, -92C-T
  Kazazian (1990) found a C-to-T change at position -92 in a Mediterranean
  HBB, -88C-T
  Orkin et al. (1984) found a C-to-T change at position -88 in an American
  black and an Asiatic Indian.
  HBB, -88C-A
  In a Kurdish Jew, Rund et al. (1989, 1991) found a C-to-A change at
  position -88.
  HBB, -87C-G
  In a Mediterranean patient, Orkin et al. (1982) found a C-to-G change at
  position -87.
  HBB, -86C-G
  In a Lebanese, Kazazian (1990) found a C-to-G change at position -86.
  HBB, -31A-G
  In a Japanese, Takihara et al. (1986) found an A-to-G change at position
  -31. Also see Yamashiro et al. (1989).
  HBB, -30T-A
  In a Turkish patient, Fei et al. (1988) found a T-to-A change at
  position -30 (a TATA box mutation). Fedorov et al. (1992) found the
  T-30A mutation in a Karachai patient with beta-thalassemia intermedia.
  HBB, -30T-C
  In a Chinese, Cai et al. (1989) demonstrated a new beta-thalassemia
  mutation: a T-to-C mutation at position -30 converting a normal TATA box
  sequence from ATAAA to ACAAA.
  HBB, -29A-G
  An A-to-G change at position -29 (a TATA box mutation) was found in an
  American black by Antonarakis et al. (1984) and in a Chinese by Huang et
  al. (1986).
  HBB, -28A-C
  In a Kurdish Jew, Poncz et al. (1983) found an A-to-C change at position
  -28 (a TATA box mutation).
  HBB, -28A-G
  In Chinese, Orkin et al. (1983) found an A-to-G change at position -28
  (a TATA box mutation).
  HBB, 3-UNT, T-C, +3
  In an American black patient, Orkin et al. (1985) found a change from
  AATAAA to AACAAA in the 3-prime untranslated portion of the gene. This
  and several others are RNA cleavage and polyadenylation mutants.
  HBB, 3-UNT, A-G, +6
  In a Kurdish patient, Rund et al. (1989, 1991, 1992) found a change from
  AATAAA-to-AATAAG in the 3-prime untranslated portion of the gene. Rund
  et al. (1992) used this and another polyadenylation mutation
  (141900.0417) to investigate the function of the poly(A) signal in vivo
  and to evaluate the mechanism whereby these mutations lead to a
  thalassemic phenotype. Analysis of RNA derived from peripheral blood
  demonstrated the presence of elongated RNA species in patients carrying
  either mutation. Other aspects of RNA processing (initiation, splicing)
  were unimpaired.
  HBB, 3-UNT, A DEL, +4
  In an Arab patient, Kazazian (1990) found deletion of an A in the
  3-prime RNA cleavage-polyadenylation signal, i.e., a change from AATAAA
  to AATAA.
  HBB, 3-UNT, G INS, +4
  In a Mediterranean patient, Jankovic et al. (1989) found a change from
  AATAA to AATGAA in the RNA cleavage-polyadenylation signal.
  HBB, 3-UNT, A-G, +5
  In a Malaysian patient, Jankovic et al. (1989) found a change from
  AATAAA to AATAGA in the RNA cleavage-polyadenylation signal.
  In an Asian Indian patient, Wong et al. (1986) found a cap site
  mutation, specifically, an A-to-C change at position 1. The first
  nucleotide of the transcript is designated the cap site; it is usually
  60-100 nucleotides 5-prime of the initiator methionine codon in the
  untranslated part of the transcript. The cap site is the nucleotide to
  which a 7-methyl-G cap is added to the mRNA transcript. The mutation
  reported by Wong et al. (1987) is the only cap site mutation reported to
  date (Kazazian, 1992).
  Wilson et al. (1990) found loss of leu-ala-his-lys at positions 141,
  142, 143, and 144 and their replacement by a gln residue. The changes
  were the result of a deletion of 9 nucleotides, namely, 2 bp of codon
  141, all of codons 142 and 143, and 1 bp of codon 144; the remaining CAG
  triplet (C from codon 141 and AG from codon 144) codes for the inserted
  In a Spanish patient, Wilson et al. (1990) found that his and val at
  positions 97 and 98 of the beta-chain had been replaced by a leu
  residue. The change resulted from the deletion of ACG in codons 97 and
  98 and the creation of a remaining triplet CTG (C from codon 97 and TG
  from codon 98) which codes for the inserted leucine residue. Wilson et
  al. (1990) considered 2 mechanisms, namely, slipped mispairing in the
  presence of short repeats, and misreading by DNA polymerase due to a
  local distortion of the DNA helix, as the basis for the small deletions
  in hemoglobin Birmingham and hemoglobin Galicia.
  In 4 generations of a family of English ancestry, Honig et al. (1990)
  found 15 persons with erythrocytosis. Elevated hemoglobin levels were
  accompanied by leftward-shifted whole blood oxygen equilibrium curves.
  Phlebotomies for relief of symptoms attributable to erythrocytosis had
  been necessary in 5 of the affected family members. In the affected
  individuals, 43% of the beta chains contained a leucine-to-phenylalanine
  substitution at position 105. Oxygen equilibrium curves demonstrated
  normal Bohr effect but decreased cooperativity.
  HBB, IVS1, T-A, +2
  Bouhass et al. (1990) described an Algerian patient who was a genetic
  compound for the mutation listed as 141900.0327 and a new mutation
  consisting of a T-to-A transversion at position 2 of IVS1.
  While investigating the mechanism of a beta-thalassemia intermedia
  phenotype in a 34-year-old Thai male, Bardakdjian-Michau et al. (1990)
  discovered a new beta-hemoglobin variant, val126-to-gly, which they
  called Hb Dhonburi. The variant was unstable but exhibited normal
  oxygen-binding properties. Pagano et al. (1991) found the same amino
  acid substitution in 3 unrelated families from southern Italy and dubbed
  it Neapolis. A GTG-to-GGG mutation was responsible for the change. The 8
  heterozygous patients showed hematologic and biosynthetic alterations of
  mild beta-thalassemia. The characteristics were very similar to those of
  Hb E (141900.0071), Hb Knossos (141900.0149), and Hb Malay
  (141900.0168), all of which have a single base substitution causing
  amino acid replacement and alternative splicing of the precursor
  beta-mRNA by activating cryptic donor sites in exon 1.
  Moghimi et al. (2004) demonstrated this variant in a family from
  northern Iran.
  Plaseska et al. (1990) found a gly-to-ala mutation at position beta119
  in a black infant and her mother. The baby was also heterozygous for Hb
  S (141900.0243). The change in hemoglobin Iowa did not affect stability
  or oxygen-carrying properties; hematologic data were normal in the
  mother and child.
  Somjee et al. (2004) described Hb Iowa in compound heterozygous state,
  not with Hb S as in the initial report, but with Hb C (141900.0038). The
  patient was an African American girl, originally diagnosed as homozygous
  Hb C during neonatal screening. Both cases indicated that there were no
  abnormal hematologic manifestations associated with this rare hemoglobin
  variant. However, in both cases, Hb Iowa was mistaken for Hb F during
  routine neonatal screening. Neonatal misidentification of Hb Iowa led to
  misdiagnosis of sickle cell disease in the patient of Plaseska et al.
  (1990) and Hb C in the patient of Somjee et al. (2004).
  In a Suriname carrier of beta-thalassemia, Losekoot et al. (1990)
  detected a frameshift insertion in the HBB gene: a single nucleotide
  (+A) at codon 47 which caused the formation of a termination codon at
  position 52.
  In a 43-year-old woman suffering from chronic anemia since the age of
  20, Wajcman et al. (1991) found this new hemoglobin variant which
  displays decreased oxygen affinity.
  This variant was detected in a cord blood sample from a Chinese newborn
  tested by IEF and reversed phase high performance liquid chromatography
  (Plaseska et al., 1990). This mutation occurs with another mutation in
  Hb Masuda (141900.0172).
  Adams et al. (1978, 1979) described a hemoglobin variant responsible for
  severe beta-thalassemia with dominant inheritance. They concluded that
  the mutation, which they referred to as Hb Indianapolis (see
  141900.0117), carried a cys112-to-arg mutation. Subsequent description
  of 2 families, which indeed carried this mutation but were minimally
  affected, prompted restudy of the original family. Both of the original
  carriers of the variants had succumbed to their severe anemia. However,
  by the use of PCR, enough DNA was recovered from a 10-year-old bone
  marrow microscope slide to sequence the third exon of the beta-globin
  gene. These studies showed substitution of arginine for leucine at
  position 106 of the beta-globin chain. In order to avoid confusion with
  the cys112-to-arg mutation, to which the name Hb Indianapolis was firmly
  attached, Coleman et al. (1991) renamed the original variant hemoglobin
  Hb Terre Haute. The dominantly inherited beta-thalassemias that are due
  to highly unstable variant beta chains, such as HB Indianapolis, result
  from the rapid catabolism of the beta chains and consequent erythroblast
  destruction within the bone marrow. These differ from the classic
  unstable hemoglobin variants in which most damage occurs to erythrocytes
  in the circulation, resulting in hemolytic anemia rather than impaired
  HBB, 3-UNT, A-G, +4
  In a Dutch patient with a mild, nontransfusion dependent
  beta-thalassemia phenotype, Losekoot et al. (1991) found a mutation in
  the cleavage-polyadenylation sequence. The mutation, AATAAA-to-AATGAA,
  was detected using denaturing gradient gel electrophoresis (DGGE) and
  direct sequencing of genomic DNA amplified by PCR.
  Kutlar et al. (1991) described a new hemoglobin variant called Hb
  Valletta, which is characterized by a threonine-to-proline substitution
  at position 87 of the beta chain. This mutation was found to be linked
  to that of the gamma-chain variant Hb F-Malta-I (142250.0014) which has
  a his-to-arg mutation at position 117 of the G-gamma chain. The 2 genes
  are 27 to 28 kb apart. No chromosomes with one or the other mutation
  alone were identified.
  In a 12-year-old black male with splenomegaly and anemia, Gaudry et al.
  (1990) found a hemoglobin variant manifest by electrophoretic
  abnormality. This unstable hemoglobin was found to have a substitution
  of aspartic acid for valine at position 54 of the beta chain.
  Thein et al. (1991) reported a patient with severe heterozygous
  beta-thalassemia characterized by large inclusion bodies and resulting
  in a single base substitution, CTG to CGG, in codon 28 in exon 1. The
  mutant hemoglobin, called Hb Chesterfield, had an unstable beta chain.
  The patient was a 34-year-old English woman who had presented at the age
  of 7 years with abdominal pain, anemia, jaundice, and
  hepatosplenomegaly. She had been transfusion-dependent since the age of
  10. Because of increasing transfusion requirements, a splenectomy was
  performed at the age of 13. Cholecystectomy was required at the age of
  Witkowska et al. (1991) found that sickle cell disease in a 3-year-old
  girl was due to compound heterozygosity for the Hb S gene and a new
  mutation called Hb Quebec-Chori. ('Chori' is an acronym for the
  Children's Hospital Oakland Research Institute.) Although the purified
  variant had gelling properties similar to those of Hb A, a mixture of it
  with Hb S resulted in a delay time of polymerization very similar to
  that of a homogeneous solution of Hb S. The sickle gene was inherited
  from the father, who was black and originally from Guyana. The new
  mutant was inherited from the mother, who was white and of
  English-Irish-French Canadian extraction. By peptide analysis, the new
  hemoglobin was found to have substitution of isoleucine for
  In a Portuguese patient suffering from a chronic hemolytic anemia,
  Wajcman et al. (1991) found an unstable hemoglobin which contained a
  his92-to-asn substitution. The variant readily loses its heme group and
  a rapid deamidation occurs in vitro, yielding an asp92 semihemoglobin.
  The oxygen affinity of the patient's red blood cells was increased,
  leading to stimulation of erythropoiesis and a macrocytic hemolytic
  disease. Harano et al. (1991) found the same unstable hemoglobin variant
  in a Japanese female with hemolytic anemia and called it Hb Isehara.
  In addition to Hb Redondo, 6 other rare Hb variants had been reported in
  which deamidation of an asn residue to an asp occurred as a spontaneous
  posttranslational modification: Hb J (Sardegna) (141850.0036), Hb J
  (Singapore) (141800.0075), Hb La Roche-sur-Yon (141900.0482), Hb Osler
  (141900.0211), Hb Providence (141900.0227), and Hb Wayne (141850.0004).
  In a Portuguese family living in Coimbra, Portugal, Tamagnini et al.
  (1991) identified a high oxygen affinity hemoglobin variant. Aspartic
  acid at residue 99 was replaced by glutamic acid in the beta chain. Two
  affected members had erythrocytosis with hemoglobin levels of 18 to 20
  g/dl. A GAT-to-GAA mutation at codon 99 represented the seventh type of
  substitution at this specific location. From a survey of mutations,
  Tamagnini et al. (1991) suggested that codons GAC(asp), GAT(asp),
  GAG(glu), and GAA(glu) are particularly susceptible to mutational
  HBB, C-A, -32
  Lin et al. (1992) described a mutation in the TATA box that has the
  sequence CATAAA and is located about 30 nucleotides upstream of the cap
  site. The mutation changed CATAAA to AATAAA.
  See Wilson et al. (1991). This hemoglobin variant combines the mutations
  present in Hb D (glu121-to-gln; 141900.0065) and in Hb Okazaki
  (cys93-to-arg; 141900.0207).
  See Lacombe et al. (1990). The asp52-to-asn mutation is also found in Hb
  Osu Christiansborg (141900.0212).
  This abnormal hemoglobin was discovered in a 75-year-old Japanese male
  with an unusually low level of Hb A(1c) (Harano et al., 1990, 1992). The
  patient was being treated for chronic renal failure. A CAC-to-CAA change
  in codon 146 was responsible for substitution of glutamine for
  histidine. Hb Kodaira was the fifth hemoglobin variant involving the
  terminal codon of the beta chain. The others are Hb Hiroshima
  (141900.0110), Hb York (141900.0305), Hb Cowtown (141900.0056), and Hb
  Cochin-Port Royal (141900.0051).
  Plaseska et al. (1991) described a new variant with a beta chain 1
  residue longer than the normal as a result of the deletion of asp, gly,
  and leu at positions 73, 74, and 75 and the insertion of ala, arg, cys,
  and gln in their place. Hb Montreal is unstable.
  See Spivak (1989).
  See Abourzik et al. (1991). This mutation is at the same nucleotide as
  that in Hb D (Los Angeles) (141900.0065).
  See Harano et al. (1991).
  A variant hemoglobin resulting from substitution of aspartic acid for
  histidine at residue 143 of the beta chain was detected in a 17-year-old
  male who had mild anemia (Moo-Penn et al., 1992).
  In a Japanese family, Hattori et al. (1992) found a GAG-to-TAG change in
  codon 90, substituting a stop codon for glutamic acid. The mutation had
  previously been found only in Japanese, the first case having been
  reported by Harano et al. (1989).
  HBB, IVS2AS, -3, C-G
  Hattori et al. (1992) identified this mutation in a Japanese patient.
  The abnormality was a substitution of guanine for cytosine at nucleotide
  848 of IVS2. This nucleotide is at position -3 in the acceptor splice
  sequence. A C-to-A mutation at the same site in an Iranian patient had
  been reported by Wong et al. (1989); see 141900.0362.
  Rund et al. (1992) used a polyadenylation mutation involving the
  deletion of 5-bp (AATAAA-to-A-----) and another mutation (141900.0383)
  to study the function of the poly(A) signal in vivo and to evaluate the
  mechanism whereby polyadenylation mutations lead to a thalassemic
  HBB, IVS1AS, G-C, -1
  In a Sicilian subject, Renda et al. (1992) identified a G-C substitution
  in the invariant AG dinucleotide at the acceptor splice site of the
  first intron. In the same nucleotide, a G-A substitution is a frequent
  cause of beta-zero-thalassemia in Egyptians (see 141900.0356). Although
  mutations in the invariant GT or AG dinucleotide splice junctions are
  known to give rise to beta-zero-thalassemia, studies were not performed
  in the specific patient reported by Renda et al. (1992) to determine
  that this was in fact a beta-zero-thalassemia mutation.
  In 3 out of 3,000 beta-thalassemia chromosomes in the Sardinian
  population, Rosatelli et al. (1992) found deletion of a single
  nucleotide G at codon 1 (GTG-to-TG), which resulted in both a frameshift
  and the formation of an in phase termination codon at codon 3. In
  addition, sequencing showed at codon 2 of the globin gene a single
  nucleotide substitution, C to T, which is a common silent substitution
  in the Mediterranean population (Orkin et al., 1982).
  In 2 members of an Arabian family from Oman, Ramachandran et al. (1992)
  discovered a leu-to-val replacement at position beta-32 by reversed
  phase high performance liquid chromatography. In 1 person, it occurred
  with Hb S and in the other with Hb A. Although Hb Muscat was slightly
  unstable, its presence had no apparent adverse effect on the health of
  its carriers.
  In a young Arabian boy living in Tunisia, Molchanova et al. (1992)
  detected a leu48-to-pro substitution in the beta chain. Since the
  parents did not have the variant, it presumably occurred by spontaneous
  mutation. It was thought not to be the cause of hemolytic anemia.
  HBB, 1-BP DEL, -G, CODON 109
  As alleles of the HBB gene producing beta-thalassemia were discovered,
  it became evident that there is a relative paucity of beta-thalassemia
  mutations in exon 3 of HBB even though this exon accounts for about 30%
  of the coding region. It appears to be a general rule that 1-bp
  frameshift mutations and nonsense mutations early in exon 3 produce a
  chronic hemolytic anemia in the heterozygous state. On the other hand,
  mutations of this type in exons 1 and 2 in the heterozygous state
  produce beta-thalassemia trait with mild phenotypic deviations from the
  normal. Kazazian et al. (1992) reported another example of this rule: in
  a 78-year-old Lithuanian Ashkenazi Jew with chronic hemolytic anemia,
  they demonstrated a -1 frameshift (-G) in codon 109. The globin was
  termed beta-Manhattan for the site of residence of the patient.
  HBB, IVS2, G-C, -1
  In 4 members of a Yugoslavian family who exhibited severe microcytosis
  and hypochromic anemia, Jankovic et al. (1992) found heterozygosity for
  a G-C mutation in the last nucleotide of IVS2. This change of the
  invariant AG dinucleotide of the acceptor splice site of intron 2
  abolished normal splicing. Two other mutations of the IVS2 acceptor
  splice site have been identified as causes of beta-zero thalassemia; see
  141900.0353 and 141900.0354.
  In a family of northern Italian descent (Brescia-Lombardia), Murru et
  al. (1992) found that a 14-year-old girl with the clinical phenotype of
  severe thalassemia intermedia had a heterozygous CTG-to-CCG change at
  codon 114 resulting in substitution of proline for leucine in the
  beta-globin chain. The resulting hemoglobin tetramer was highly unstable
  and precipitated to form inclusion bodies in peripheral red blood cells.
  The unusually severe phenotype present in this heterozygote was thought
  to be explained by the coinheritance of a triple alpha-globin locus.
  In a 29-year-old female of Irish descent with thalassemia-like anemia
  during her first pregnancy, deCastro et al. (1992) found no gross
  structural alteration on Southern blot analysis of the globin genes but
  found an alpha:beta globin chain synthesis ratio of 0.91 (control =
  0.94). Because they suspected an unstable hemoglobinopathy and because
  many of these disorders are due to point mutations in exon 3 of the
  beta-globin chain, they performed PCR-SSCP analysis, which showed an
  abnormality. Sequencing demonstrated a T-to-C transition at codon 114
  resulting in a leucine-to-proline substitution. They called the
  hemoglobin variant Durham-N.C. to distinguish it from hemoglobin Durham,
  named for the city in England. The mutation created a novel MspI
  restriction site in exon 3 of the HBB gene. DeCastro et al. (1994)
  demonstrated that this hemoglobinopathy, like several others within exon
  3 of the beta-globin gene, e.g., Hb Showa-Yakushiji (leu110-to-pro;
  141900.0262), result in a thalassemic and/or hemolytic phenotype with
  moderately severe microcytic anemia inherited as an autosomal dominant.
  Kim et al. (2001) described the molecular and hematologic
  characteristics of a Korean family with a dominantly inherited
  beta-thalassemia. Carriers were characterized by moderate anemia,
  hypochromia, microcytosis, elevated Hb A2 and Hb F levels, and
  splenomegaly. A CTG (leu) to CCG (pro) change at codon 114 of the HBB
  was demonstrated. They referred to the abnormal hemoglobin as Hb
  HBB, C-T, -90
  In an asymptomatic Portuguese female, Faustino et al. (1992) found
  heterozygosity for a C-to-T transition at position -90 in the proximal
  CACCC box.
  In a Portuguese family with 'dominant' thalassemia intermedia, Faustino
  et al. (1992) found deletion of nucleotides 4 and 5 (AG) in IVS2 of the
  HBB gene, converting GTGAGT to GTGTCT.
  In a 5-generation Portuguese family, Faustino et al. (1998) described an
  autosomal dominant form of beta-thalassemia intermedia. Carriers showed
  moderate anemia, hypochromia, microcytosis, elevated Hb A2 and Hb F,
  splenomegaly, hepatomegaly, and inclusion bodies in peripheral red blood
  cells after splenectomy. The molecular basis was found to be deletion of
  2 nucleotides, AG, within the 5-prime splice site consensus sequence of
  intron 2 of the HBB gene. The fourth and fifth nucleotides in the
  sequence GTGAG were deleted. Reticulocyte RNA studies performed by
  RT-PCR and primary extension analysis showed 3 abnormally processed
  transcripts, which, upon sequencing, were shown to correspond to (1)
  skipping of exon 2, and (2) activation of 2 cryptic splice sites
  (between codons 59 and 60), and at nucleotide 47 in the second intron.
  In vitro translation studies showed that at least 1 of these aberrant
  mRNA species is translated into an abnormally elongated peptide whose
  cytotoxic properties could, in part, be causing the atypical dominant
  mode of inheritance observed in this family. Faustino et al. (1998)
  suggested that this elongated beta chain is unable to combine with an
  alpha-globin chain to form a functional hemoglobin molecule. Its
  degradation would, then, exhaust the proteolytic defense mechanism of
  the erythroid precursors, leading to inefficient proteolysis of the free
  alpha chains in excess.
  Wajcman et al. (1992) demonstrated that Hb Duino, an unstable
  hemoglobin, carries 2 point mutations, the his92-to-pro mutation of Hb
  Newcastle (141900.0197) and the arg104-to-ser mutation of Hb Camperdown
  (141900.0042). Family studies demonstrated that the Hb Newcastle
  abnormality was a de novo mutation of a gene already carrying the Hb
  Camperdown substitution. One member of the Italian family studied by
  Wajcman et al. (1992) had hemolytic anemia.
  Divoky et al. (1992) analyzed the hemoglobin of a child of German
  descent living in the former German Democratic Republic and exhibiting
  typical clinical features of beta-thalassemia intermedia. One of his
  chromosomes 11 and 1 of his mother's carried a GTG-to-ATG mutation at
  codon 18, resulting in the replacement of a valine residue by a
  methionine residue. Called Hb Baden, the newly discovered beta-chain
  variant represented only 2 to 3% of the hemoglobin in both the patient
  and his mother because of the presence of an IVS1 +5 G-to-C thalassemic
  mutation (141900.0357) on the same chromosome. On the other chromosome,
  inherited from the father, the boy carried the val126-to-gly mutation of
  Hb Dhonburi (141900.0393), which itself is slightly unstable and
  associated with mild thalassemic features.
  Liu et al. (1992) accidentally detected 2 abnormal hemoglobins by cation
  exchange high performance liquid chromatography performed with an
  automated system designed to quantitate Hb A1c in blood samples from
  patients with diabetes mellitus. The variants eluted together with the
  fast-moving Hb A1c. One of the variants, found in 4 healthy, apparently
  unrelated adults, involved a change from a histidine to a leucine
  residue at position 2 of the beta chain. The second variant was
  identical to Hb Sherwood Forest (141900.0261).
  In a typical beta-thalassemia carrier of Italian descent, Saba et al.
  (1992) demonstrated a G-to-A transition in the initiation codon of the
  HBB gene, producing a substitution of isoleucine for methionine. The
  absence of the initiation methionine led to defective beta-globin mRNA
  translation and probably determined the complete absence of beta-chain
  production. Indeed, initiation of translation may have occurred at the
  first downstream ATG sequence, which is located at codon 21-22; the
  resulting out-of-frame reading probably terminates at the new UGA
  termination codon at codon 60-61. Initiation codon mutations previously
  described in both the alpha (141850.0022) and beta (141900.0344) globin
  genes all result in complete inactivation of the affected globin gene.
  In 7 members of 3 generations of a family living in northern Sweden,
  Landin et al. (1995) found an initiation codon mutation ATG-to-ATA of
  the HBB gene. The mutation changed the initiation codon from methionine
  to isoleucine and resulted in a beta-zero-thalassemic phenotype. The
  affected family members all presented hematologic findings typical for
  the beta-thalassemic trait, with slight anemia, marked microcytosis, and
  increased levels of Hb A2. See 141900.0345 for an initiation codon
  mutation ATG-to-ACG, which changes methionine to threonine.
  In the course of quantification of Hb A(1c) in a 48-year-old Swedish
  woman, Landin (1993) discovered a variant hemoglobin that comprised
  approximately 39% of the total hemoglobin. A study demonstrated a
  GAT-to-CAT mutation in codon 21, corresponding to an asp21-to-his
  substitution. As predicted from the location of the substitution in the
  molecule, it was not associated with any overt hematologic
  During a routine hematologic evaluation of a 1-year-old boy and his
  father, Broxson et al. (1993) found a variant hemoglobin that produced a
  band on electrophoresis in the same position as that for sickle
  hemoglobin. Screening of other family members showed that the paternal
  grandmother and an uncle also had the variant. Amino acid analysis
  demonstrated that glycine at position 83 of the beta-globin chain had
  been substituted by arginine. This gly83 is an external residue with no
  significant inter- or intra-molecular contacts, and mutation at this
  residue would not be expected to cause any changes in the functional
  properties of the variant.
  In a healthy 36-year-old male of Ethiopian descent with normal
  hematologic findings, Molchanova et al. (1993) found a hemoglobin
  variant with electrophoretic mobility on cellulose acetate like that of
  Hb S. DNA studies demonstrated a GAC-to-CAC transversion leading to an
  asp79-to-his amino acid substitution.
  Pistidda et al. (2001) identified the same mutation in a Caucasian in
  the Sassari district of Sardinia.
  Duwig et al. (1987) found a new unstable hemoglobin in a boy of 9 years
  hospitalized for hematuria and diffuse pains. Clinical examination
  demonstrated isolated splenomegaly without hepatomegaly or adenopathy.
  He was anemic and the variant hemoglobin constituted 30% of total
  hemoglobin. Molecular studies revealed a substitution of arginine for
  In 4 apparently unrelated French families, Wajcman et al. (1993) found 5
  patients carrying a hemoglobin variant associated with moderate
  erythrocytosis. The structural abnormality was a replacement of
  phenylalanine-103 by isoleucine. The residue involved was the same as
  that in Hb Heathrow (141900.0102), which is a phe103-to-leu
  substitution. The increase in oxygen affinity is much lower in Hb Saint
  Nazaire than in Hb Heathrow. The replacement of phenylalanine G5, which
  is located within the heme pocket, by leucine abolishes several contacts
  between heme and globin and leads to an environment of the heme with
  similarities to that observed in myoglobin. In contrast, the replacement
  of G5 by an isoleucine is likely to introduce less structural
  In a Czech family, Divoky et al. (1993) found a GCC-to-GAC mutation in
  codon 115 of the beta-globin gene as the cause of dominant
  beta-thalassemia trait. The variant hemoglobin was markedly unstable. A
  mother and daughter, who were heterozygotes, showed moderate anemia,
  reticulocytosis, nucleated red cells, target cells, Heinz body
  formation, and splenomegaly. Both had marked increase in fetal
  hemoglobin synthesis.
  Fay et al. (1993) described hemoglobin Manukau in 2 brothers presenting
  with nonspherocytic hemolytic anemia who became transfusion-dependent by
  6 months of age. The severity of clinical expression seemed to be
  modulated by coexisting alpha-thalassemia. The brothers had a Niuean
  mother and a New Zealand Maori father. A second unusual feature was a
  modification of beta-141 leu, which appeared to be deleted because
  posttranslational modification had changed leu-141 to a residue
  (probably hydroxyleucine) that was not detected by standard amino acid
  analysis and sequencing methods. The same feature occurs in Hb Coventry
  In a 41-year-old man in Spain with severe erythrocytosis, Wajcman et al.
  (1993) found an electrophoretically silent hemoglobin variant with very
  high oxygen affinity and markedly reduced cooperativity. The structural
  abnormality was determined by mixing normal and abnormal beta chains,
  isolating the abnormal tryptic peptide by reversed-phase HPLC, and
  sequencing the peptide by mass spectrometry. Serine-89 was replaced by
  During routine hematologic investigation of a 44-year-old man, Owen et
  al. (1993) found a novel hemoglobin with high oxygen affinity and a
  substitution of glycine for tryptophan-37. This change would be expected
  to result in a destabilization of the deoxyhemoglobin form because of
  the reduced number of hydrogen bonds, salt bridges, and van der Waal
  contacts between the alpha-1 and beta-2 chains. Hemoglobin was 16.3
  g/dL. The variant constituted 29% of the hemoglobin, indicating either
  reduced stability of the nascent Hb Howick chain or an impaired
  expression level.
  Stabler et al. (1994) reported a 16-year-old white boy from Denver,
  Colorado, in whom cyanosis of the skin, lips, mucous membranes,
  conjunctivas, and nail beds was noted at the time of a dental
  extraction. The mother also had lifelong cyanosis and, although
  asymptomatic, had had severe anemia during pregnancy. The maternal
  grandmother and maternal aunt had chronic cyanosis and mild anemia. No
  abnormal hemoglobin band separate from that of hemoglobin A was found on
  electrophoresis, HPLC, and isoelectric focusing. However, a heat test
  showed hemoglobin instability, and O2 studies disclosed an appreciably
  right-shifted dissociation curve. On chromatography, the new
  variant--hemoglobin Denver--was found to carry a substitution of serine
  for phenylalanine at position 41 in the beta chain. In addition to
  reduction in O2 affinity, hemoglobin Denver was accompanied by moderate
  reticulocytosis and mild anemia. The corresponding substitution in the
  hemoglobin gamma gene is found in hemoglobin F (Cincinnati) (HBG2;
  142250.0041) and is associated with cyanosis.
  Rahbar et al. (1991) discovered Hb Beckman, an alanine-to-glutamic acid
  mutation at position 135 of the HBB gene, in a 32-year-old African
  American woman with chronic anemia and microcytosis and a palpable
  spleen. While substitution of proline at position 135 (Hb Altdorf;
  141900.0007) results in an unstable hemoglobin variant with increased
  affinity for oxygen, substitution of glutamic acid has a reverse effect,
  i.e., Hb Beckman has reduced oxygen affinity.
  A de novo mutation was reported by Park et al. (1991) in an 8-year-old
  boy who presented with symptoms of mild anemia and was found to be
  icteric with moderate splenomegaly. PCR followed by DNA sequencing of
  the HBB gene demonstrated that the mutation results in a deletion of
  valine (GGT) at amino acid position 33 or 34 without altering the
  reading frame in the remainder of the subunit. The deletion appears to
  disrupt the globin structure badly, producing a clinical phenotype of
  beta-thalassaemia resembling that of an ineffective erythropoiesis.
  Coleman et al. (1993) discovered Hb Medicine Lake in a 17-month-old
  Caucasian female with hepatosplenomegaly and severe,
  transfusion-requiring hemolytic anemia. Although an abnormal hemoglobin
  could not be detected by electrophoresis, isoelectric focusing, or HPLC,
  DNA sequencing of the beta globin genes from the proband revealed both a
  codon 98 GTG-to-ATG transition that codes for the val-to-met mutation of
  Hb Koln (141900.0151) and a codon 32 CTG-to-CAG transversion coding for
  a leu-to-gln replacement. The hydrophilic glycine residue of Hb Medicine
  Lake contains an uncharged polar side chain, which distorts the
  3-dimensional configuration of the globin; this would be predicted to
  cause instability but no shift in electrophoretic mobility.
  During the course of a genetic survey of the first-year students at a
  London Medical School, Hb D (Neath) was discovered in an 18-year-old
  Caucasian female by Welch and Bateman (1993). In the variant HBB chain,
  the glutamic acid residue at position 121 is replaced with alanine.
  Krishnan et al. (1993, 1994) reported a val-to-phe mutation at position
  11 of the HBB chain in 6 members in 3 generations of a family of
  Hungarian-American descent. The proband had primary pulmonary
  hypertension, and other members of the family were mildly anemic. At
  least one other Hb variant, Hb Warsaw (141900.0257), has been reported
  to be associated with pulmonary hypertension. Hb Washtenaw is slightly
  unstable and has a low oxygen affinity.
  Molchanova et al. (1993) discovered Hb Alesha in a 15-year-old Russian
  patient with severe hemolytic disease, anemia, splenomegaly, Heinz body
  formation, and continued requirement for blood transfusions despite a
  splenectomy at age 3. PCR amplification and sequence analysis of the
  hemoglobin beta gene indicated a GTG-to-ATG point mutation at codon 67,
  causing a valine-to-methionine transition. Molchanova et al. (1993)
  postulated that the replacement of valine by the larger methionyl
  residue significantly reduces the stability of the hemoglobin molecule
  by disrupting the apolar bonds between the valine and the heme group.
  Girodon et al. (1992) reported Hb Dieppe in a 31-year-old French female
  with chronic anemia. DNA sequencing revealed a missense mutation
  (GAG-to-CGG) at position 127 of the beta-globin gene, causing a
  glutamine-to-arginine transition. The hemoglobin variant is highly
  unstable; the introduction of a positively charged hydrophilic residue
  at position 127 disrupts the tight contacts between the alpha and beta
  Hb Higashitochigi was discovered by Fujisawa et al. (1993) in a
  2-year-old Japanese boy with chronic cyanosis. The variant is missing a
  glycine residue, due to a deletion of 3 nucleotides in the genomic DNA
  (codons 24-25: GGTGGT-to-GGT). It is likely that the absence of glycine
  indirectly distorts the heme pocket, causing decreased oxygen binding of
  the beta chain and impaired oxygen release of the normal alpha chain in
  the tetrameric molecule.
  Landin et al. (1994) added another example to the more than 40
  hemoglobin variants with increased oxygen affinity associated with
  erythrocytosis. In 3 generations of the family of a 23-year-old male
  from Trollhaettan in Sweden, Landin et al. (1994) observed
  heterozygosity for a GTG-to-GAG transition at codon 20 that predicted a
  val-to-glu substitution, which was confirmed at the protein level. The
  mutation occurred in the same codon as hemoglobin Olympia (141900.0210),
  which shows a val20-to-met amino acid substitution.
  In a variant hemoglobin designated Hb Tyne, Langdown et al. (1994)
  observed a CCT-to-TCT change in codon 5 predicting substitution of
  serine for proline. The variant was first found in a 66-year-old
  diabetic male after an inappropriately low level of glycosylated
  hemoglobin was detected by enzyme immunoassay, and confirmatory ion
  exchange high performance liquid chromatography revealed the presence of
  an abnormal hemoglobin. Consequently, Langdown et al. (1994) identified
  the same mutation in an apparently unrelated diabetic male. Neither
  occurrence of the variant was associated with any abnormal hematologic
  Coleman et al. (1995) investigated the molecular basis of
  transfusion-dependent hemolytic anemia in a Caucasian female infant who
  rapidly developed the phenotype of beta-thalassemia major. Both the
  father and mother were normal hematologically. The DNA sequence of one
  HBB gene demonstrated 2 mutations, one for the moderately unstable Hb
  Koln (141900.0151) and another for a novel leu32-to-gln change resulting
  from a CTG to CAG transversion. The new hemoglobin was called Hb
  Medicine Lake. The hydrophilic gln32 has an uncharged polar side chain
  that may distort the B helix and provoke further molecular instability.
  Biosynthesis studies of this mutation showed a deficit of beta-globin
  synthesis with early loss of beta-globin chains. Coleman et al. (1995)
  pointed to 14 previously described hemoglobin variants with 2 mutations
  in the same polypeptide chain. Most of these rare disorders had probably
  arisen via homologous crossing over. Such a mechanism, however, could
  not account for the Hb Medicine Lake, since neither parent had a
  detectable abnormal hemoglobin gene. Therefore, it was presumed that
  this was a true double de novo mutation.
  Harano et al. (1995) used the designation Hb Yaizu, after the city where
  the carrier lived, for a new beta-chain variant found in a Japanese
  female who was apparently healthy. Isoelectric focusing showed an
  abnormal hemoglobin band between the normal A2 and A bands. An
  asp79-to-asn amino acid substitution was demonstrated.
  HBB, IVS2AS, G-A, -1
  Curuk et al. (1995) described an American family of English-Scottish
  descent in which 6 members were found to be heterozygous for
  beta-thalassemia. Sequencing of the HBB gene showed a G-to-A transition
  at the splice acceptor site of the second intron, changing the canonical
  AG to AA. Nucleotide 850 was involved; Curuk et al. (1995) commented
  that a G-to-C change in the same nucleotide had been found in a
  Yugoslavian family, whereas a frameshift due to deletion of nucleotide
  850 was found in an Italian family. All 3 nucleotide changes lead to
  beta-zero thalassemia and are rare in the populations in which they were
  Gurgey et al. (1995) observed a highly unstable hemoglobin variant in a
  5-year-old Turkish girl with severe hemolytic anemia without Heinz body
  formation. A modest increase in liver and spleen size was present and
  level of Hb F was 33%. The variant could not be observed in red cells
  and was only detected through sequencing of the amplified beta-globin
  gene and also by hybridization with specific oligonucleotide probes. The
  variant was presumably a de novo mutation, since the parents were
  normal. Smears from bone marrow aspirates showed numerous inclusion
  bodies in erythroblasts and, as a result, erythroid hyperplasia. It was
  suggested that this hemoglobin variant was unstable and readily lost its
  heme group because one of the heme-binding sites had been lost and that,
  as a result, it precipitates in erythroblasts, thus interfering with the
  maturation process and causing severe anemia.
  In 2 sibs with polycythemia in a French family, Wajcman et al. (1995)
  found a de novo ala140-to-val mutation. The hemoglobin displayed
  increased oxygen affinity, thus explaining the polycythemia. Both
  parents were phenotypically normal and study of polymorphic markers from
  several chromosomes were consistent with paternity. Since 2 brothers
  were affected, it was considered likely that the mutation had occurred
  in the germline of the father.
  In a 22-year-old Caucasian female, known to be anemic from early
  childhood and showing scleral subicterus and slightly enlarged spleen on
  physical examination, Vassilopoulos et al. (1995) described a new
  unstable hemoglobin variant with reduced oxygen affinity. A phe45-to-cys
  amino acid substitution was found in beta-globin. The other chromosome
  11 carried the gln39-to-ter (141900.0312) mutation that causes
  beta-zero-thalassemia. The new variant was named for the Greek city
  where the patient was born.
  In a 73-year-old female of Dutch descent, Lafferty et al. (1995) found
  that a high oxygen affinity hemoglobin variant resulted from an
  AAT-to-TAT transversion of codon 139, resulting in an asn139-to-tyr
  amino acid substitution. See 141900.0092 for the asn139-to-asp mutation
  and 141900.0108 for the asn139-to-lys mutation involving the same codon.
  During the assay of glycated hemoglobin by HPLC, Harano et al. (1995)
  identified a new hemoglobin named Hb Nakano for the district of Tokyo
  where healthy, 46-year-old Japanese woman lived and showed that it was
  due to a change of codon 8 from lysine to methionine. See 141900.0135
  for the lys8-to-gln mutation, 141900.0191 for the lys8-to-glu mutation,
  and 141900.0237 for the lys8-to-thr mutation.
  Frischknecht et al. (1996) found a new hemoglobin variant in the course
  of investigation of mild erythrocytosis. Mutation mapping of the
  beta-globin gene by PCR and denaturing gradient gel electrophoresis
  (DGGE) followed by sequence analysis revealed a C-to-A transversion at
  codon 38, predicting a thr38-to-asn substitution. In contrast to the
  other known mutation at codon 38, thr38-to-pro (known as Hb Hazebrouck;
  141900.0101), Hb Hinwil was found to be stable and showed elevated
  oxygen affinity.
  Lacan et al. (1996) described an unstable variant hemoglobin with high
  oxygen affinity responsible, in the steady state, for an apparently
  well-compensated chronic hemolytic anemia. The defect was shown to be a
  leu96-to-pro substitution in the HBB gene. The hemoglobin was named for
  the hospital in Lyon, France where the patient was observed. This
  electrophoretically neutral hemoglobin was found as a de novo case in a
  6-year-old girl suffering from severe anemia with hemolysis and
  transient aplastic crisis following infection by parvovirus B19.
  HBB, 2-BP DEL, CODONS 38-39, FS 
  In 3 members of an indigenous Belgian family with beta thalassemia,
  Heusterspreute et al. (1996) found a deletion of 2 nucleotides, CC, from
  codons 38 and 39. The mutation eliminates an AvaII restriction site and
  so can be routinely investigated by AvaII digestion of amplified DNA.
  In a 46-year-old Japanese male with plethora and erythrocytosis, Ohba et
  al. (1996) found a lys82gln amino acid substitution in the beta-globin
  chain. A son also had erythremia due to this hemoglobin variant.
  In a 27-year-old man of Italian origin living in Belgium investigated
  because of mild polycythemia with microcytosis, Kiger et al. (1996)
  found that the hemoglobin had a negatively charged residue near the
  distal histidine and a ala62-to-asp substitution. The variant was called
  Hb J-Europa, presumably because it was found in the proband during a
  systematic physical examination performed before employment at the
  headquarters of the European Economic Community (EEC) in Luxembourg.
  Lacan et al. (1996) found this mildly unstable variant in a French
  family without hematologic or clinical features. Although the
  substitution involves the same residue as in Hb E (141900.0071), the new
  sequence in this case did not create an additional out-of-frame splice
  site. The mutated chain was, therefore, normally synthesized.
  Miranda et al. (1996) described Hb Camperdown in a 24-year-old Brazilian
  woman of Italian origin. Although carriers do not show significant
  clinical alterations, Hb Camperdown is considered an unstable Hb.
  HBB, 3-BP INS, CGG, CODON 30+ 
  Negri Arjona et al. (1996) described a Spanish family with a dominant
  type of beta-thalassemia. Carriers were characterized by mild anemia,
  hyperchromia, microcytosis, elevated Hb A2 and Hb F levels,
  reticulocytosis, and splenomegaly. They found that the molecular basis
  was the introduction of a CGG triplet between codons 30 and 31 of the
  HBB gene; this was determined by sequencing of amplified DNA and
  confirmed by dot-blot analysis. The abnormal mRNA was stable and present
  in quantities similar to that of normal mRNA. The abnormal mRNA
  translated into a beta-chain that was 147 amino acid residues long and
  carried an extra arginine residue between residues 30 and 31. The
  abnormal beta chain may be unstable and does not bind to the
  alpha-chain. It probably is continuously digested by proteolytic enzymes
  in red cell precursors in the bone marrow. The abnormal chain probably
  binds haem that is excreted after proteolysis causing a darkening of
  urine, which was a clinical characteristic of the disorder. The
  insertion occurred at the 3-prime end of IVS1 and the 5-prime end of
  exon 2. The insertion may have an addition of CGG between codons 30 and
  31 or an insertion of GGC between IVS1 129/130.
  Rodriguez Romero et al. (1996) discovered an abnormal beta-chain
  hemoglobin Hb Costa Rica, or beta-his77arg, in a healthy young Costa
  Rican female. This stable hemoglobin, termed Hb Costa Rica, was present
  in only 6 to 8% of hemoglobin and was not observed in any relative (the
  father was not available for study). The expected CAC-to-CGC mutation
  could not be detected in genomic DNA. Smetanina et al. (1996) presented
  convincing evidence that the CAG-to-CGC mutation at codon 77 of the HBB
  gene had occurred as a somatic mutation during embryonic development and
  resulted in mosaicism with only 6 to 8% of the abnormal Hb Costa Rica in
  circulating red cells. Bradley et al. (1980) had described an instance
  of gonadal mosaicism accounting for an unusual pedigree pattern in a
  family with Hb Koln (141900.0151). Smetanina et al. (1996) incorrectly
  stated that theirs was the first example of mosaicism in a hematopoietic
  HBB, 1-BP INS, CODON 20/21, FS 
  Beta-thalassemia alleles are uncommon among Ashkenazi Jews as compared
  with Sephardic Jews and other populations. Oppenheim et al. (1993)
  described a rare allele, a single-base insertion resulting in a
  frameshift at codon 20/21, in an Ashkenazi Jewish proband living in
  Israel. Martino et al. (1997) independently discovered this allele
  (called fs20/21 by them) in a Montreal Ashkenazi pedigree and
  investigated the possibility of genealogic connections between the 2
  families. They showed by analysis of the mutation and the associated
  marker haplotype that the Israeli and Montreal probands appeared to be
  identical by descent and certainly had identity by state at the HBB
  locus. Genealogic reconstruction suggested that the 2 families had a
  shared origin in time and space.
  Ohba et al. (1997) reported the fifth variant with retention of the
  initiator methionine and partial acetylation. The proband, a 37-year-old
  Japanese male, was subjected to detailed studies because of an
  unexpectedly high HbA1c value on cation exchange high performance liquid
  chromatography. The findings of their subsequent studies, as well as
  previous reports, suggested that retention of the initiator methionine
  and acetylation have no physiologic or pathologic significance, at least
  on human hemoglobin. The authors found that the variant hemoglobins were
  not unstable in in vitro tests. Ohba et al. (1997) stated that they must
  be almost as stable as normal HbA in vivo because they comprise over 40%
  of total Hb in the peripheral blood. The 4 previously reported Hb
  variants with retention of initiator methionine were Hb Thionville
  (141800.0168), Hb Marseille (141900.0171), Hb Doha (141900.0069), and Hb
  South Florida (141900.0266).
  Waye et al. (1997) described a beta-thalassemia trait in a Caucasian
  woman of British descent living in Ontario, Canada. The 48-year-old
  woman presented with typical high Hb A2 beta-thalassemia trait. All
  known family members were of British ancestry. Her father had normal
  hematologic indices and her mother was deceased. There was no family
  history of anemia. Direct nucleotide sequencing demonstrated a complex
  frameshift mutation due to deletion of 5 nucleotides (AGTGA) and
  insertion of 1 nucleotide (T) at codons 72/73 of the HBB gene. This
  introduced a premature stop codon (TGA) at codon 88, resulting in
  In a Lombardy family (from Gambara, near Brescia in Northern Italy),
  Ivaldi et al. (1997) described a 45-year-old man and his 2 daughters who
  carried an abnormal hemoglobin resulting in modest erythrocytosis and
  mild, compensated hemolysis with slight splenomegaly. The abnormal
  hemoglobin represented about 52% of the total hemoglobin, and was shown
  to be stable by the isopropanol test. Sequencing demonstrated a change
  in the HBB gene of codon 82 from AAG (lys) to GAG (glu) in heterozygous
  HBB, IVS1AS, A-G, -2 
  Waye et al. (1998) studied the hemoglobin of a 37-year-old woman who
  presented during pregnancy with the beta-thalassemia trait. The father
  and mother were Sephardic Jews whose families had lived for many
  generations in Tangiers and Gibraltar, respectively. The HBB gene was
  found to have a single basepair substitution at codon 30: AGG (arg) to
  GGG (gly). The mutation changed the sequence immediately upstream of the
  5-prime splice junction of the first intron: A-to-G at position -2 of
  IVS1. The authors stated that although mutations had been found at
  positions -1 and -3 of IVS1, no mutation had been described at the -2
  position. The authors thought it unlikely that an arg30-to-gly
  substitution was responsible for the abnormality and favored the
  possibility that the mutation impaired the normal splicing of the
  beta-globin pre-mRNA.
  Li et al. (1998) identified the same mutation in a Chinese man whose
  wife carried the 4-bp deletion at codons 41/42 (141900.0326) that is a
  common beta-thal mutation in Japanese. Their son had died of severe
  anemia at age 4 and the authors speculated that he had
  beta-0-thalassemia due to compound heterozygosity for these mutations.
  HBB, 1-BP INS, T, CODON 26 
  Hattori et al. (1998) identified a new beta-thalassemia allele in a
  31-year-old Japanese man who was found to have microcytosis and
  erythrocytosis during a health check-up. His red blood cell count was
  6.53 x 10(12) per liter. The HBB gene in 1 allele was found to have an
  insertion of T at codon 26: GAG-to-GTAG. The frameshift mutation was
  expected to result in beta-zero-thalassemia because the translation of
  the abnormal mRNA produced a peptide with an abnormal amino acid
  sequence from codon 26 to 42 where it terminates. Such a truncated
  peptide of 42 residues would be immediately eliminated by proteolysis.
  Codon 26 is involved in the consensus sequence for cryptic splicing at
  codon 25. The insertion of T at codon 26 breaks the consensus sequence
  and is unlikely to affect the alternative splicing. Results of SSCP
  analysis indicated that the patient was heterozygous for the frameshift.
  Hoyer et al. (1998) described a new hemoglobin variant called Hb Silver
  Springs which resulted from a CAG (gln)-to-CAC (his) change at codon 131
  of the beta chain. It was detected only by cationic exchange high
  performance liquid chromatography. This was the fifth reported
  substitution at codon 131. The variant did not appear to have any
  clinical or hematologic manifestations. It was found in 6 African
  Americans from 4 presumably unrelated families.
  In investigating the nature of the unique hemoglobin variant that caused
  a spurious increase in glycated hemoglobin, Hb A(1c), Elder et al.
  (1998) found a CAC-to-TAC mutation in the HBB gene that resulted in a
  his143-to-tyr substitution in the beta-globin peptide. This amino acid
  substitution affected an important 2,3-diphosphoglycerate binding site
  and slightly increased the oxygen affinity of the hemoglobin variant.
  Despite the slight increase in oxygen affinity, the mutation was without
  hematologic effect, and its only clinical significance was that it
  coeluted with Hb A(1c) on ion-exchange chromatography and compromised
  the use of this analyte to monitor the treatment of diabetes mellitus.
  The variant was encountered in 4 unrelated persons of Irish or
  Scottish-Irish ancestry.
  Gilbert et al. (2000) reported 2 unrelated cases of Hb Old
  Plaseska-Karanfilska et al. (2000) found the same mutant hemoglobin in a
  72-year-old Korean woman with type II diabetes (125853).
  By globin chain electrophoresis, Grignoli et al. (1999) detected a novel
  silent hemoglobin variant in a 4-year-old Caucasian Brazilian boy of
  Italian descent, and in his mother. Sequencing of the HBB gene revealed
  a G-to-A transition at the first position of codon 34, resulting in a
  val-to-met substitution. In the boy, this variant was found to be
  associated with Hb Hasharon (141850.0012) and alpha-thalassemia-2
  (rightward deletion).
  HBB, 4-BP DEL/1-BP INS, CODONS 138/139, GCTA/T 
  Van den Berg et al. (1999) identified a novel Hb B variant, termed Hb
  Nijkerk, in a Caucasian Dutch girl who was slightly icteric at birth and
  developed hemolytic anemia and hepatosplenomegaly at about 5 months of
  age. Red cell transfusions were necessary every 3 to 4 weeks.
  Erythromorphology was markedly abnormal, with large numbers of red cells
  with inclusion bodies. Splenectomy was performed at the age of 18
  months, after which the need for transfusions decreased and they were
  finally discontinued. Although still anemic, the child's growth was
  otherwise normal. Repeated hemoglobin electrophoresis on cellulose
  acetate revealed no abnormalities. At the age of 17 years, a minor
  abnormal band, migrating slightly faster than Hb A2, was detected on
  starch gel electrophoresis. Sequencing of the HBB gene revealed
  heterozygosity for a 4-bp deletion (GCTA) in combination with a 1-bp
  insertion (T) at codons 138/139. This event eliminated 2 amino acids
  (ala and asn) and introduced a new residue (tyr) into the protein. The
  parents did not carry the mutation and paternity analysis showed no
  discrepancies, indicating that Hb Nijkerk should be considered as a de
  novo event.
  Hojas-Bernal et al. (1999) identified a novel Hb B gene variant, termed
  Hb Chile, in a 57-year-old Native American living in Chile who was known
  to be chronically cyanotic. He was hospitalized for elective surgery of
  left pyeloureteral stenosis. Prior to surgery, he was given
  sulfonamides. Surgery was terminated when the dark color of his blood
  was noted. Arterial oxygen saturation was 80%. His blood contained 18%
  methemoglobin. Repeated intravenous methylene blue was given for the
  methemoglobinemia but to no avail. Sulfhemoglobin was not increased.
  Subsequently, an acute episode of hemolytic anemia occurred. Red cell
  glucose-6-phosphate dehydrogenase and methemoglobin reductase were
  normal. The patient's father and 1 of his 2 children also showed
  cyanosis. Tryptic digestion of the beta-globin chain and subsequent
  chromatography revealed an abnormal beta-T-3 peptide; sequencing
  revealed a leu-to-met substitution at position 28, predicted to be
  caused by a CTG-to-ATG transversion in the HBB gene. Hojas-Bernal et al.
  (1999) concluded that Hb Chile is an unstable hemoglobin that forms
  methemoglobin in vivo spontaneously at an accelerated rate and
  predisposes to drug-induced hemolytic anemia.
  By chromatographic measurement of glycated Hb in a 90-year-old woman of
  French origin, Wajcman et al. (1998) identified a novel hemoglobin
  variant, termed Hb Tende, that showed a moderate increase in oxygen
  affinity. Sequencing of the HBB gene revealed a CCA-to-CTA transition,
  resulting in a pro124-to-leu substitution. Three hemoglobin variants at
  amino acid 124 had been previously described: Hb Tunis (pro124 to ser;
  141900.0288) is asymptomatic; Hb Khartoum (pro124 to arg; 141900.0148)
  is mildly unstable; and Hb Ty Gard (pro124 to gln; 141900.0289) is
  responsible for increased oxygen affinity leading to erythrocytosis.
  Wajcman et al. (1998) suggested that the absence of erythrocytosis in
  the Hb Tende carrier whom they studied was likely due to the relatively
  low proportion of abnormal Hb (34%), possibly explained by the mild
  instability revealed by the isopropanol test, and to the normal
  cooperativity of the variant.
  Wajcman et al. (1992) identified Hb La Roche-sur-Yon, an unstable
  hemoglobin variant resulting from a leu81-to-his substitution in the HBB
  gene. The variant displayed a moderately increased oxygen affinity. in
  addition to the substitution at beta-81, about half the abnormal
  hemoglobin carried a deamidation of the neighboring asparagine residue
  at beta-80. The authors concluded that the deamidation depends not only
  on the flexibility of the polypeptide region but also on the presence of
  a neighboring histidine residue to catalyze the reaction. See also Hb
  Redondo (141900.0404).
  In a family originating from Iraq, Deutsch et al. (1999) identified a
  novel beta-chain silent variant, a change of codon 10 from GCC to GTC
  (ala10 to val), in association with thalassemia. The variant, which they
  designated Hb Iraq-Halabja, gave a normal oxygenation curve, a normal
  heterotopic action of 2,3-DPG, and normal heat stability and isopropanol
  precipitation tests. The variant showed a clear difference in migration
  properties compared to normal beta chain only when run on PAGE urea
  Triton. The codon involved in Hb Iraq-Halabja is the same as that mutant
  in Hb Ankara (141900.0009), in which the substitution is ala10 to asp.
  Agarwal et al. (1999) found an A-to-G transition in exon 1 of the HBB
  gene at codon 8 which resulted in a lys8-to-arg amino acid substitution.
  This change was associated with a splice mutation and was speculated to
  produce a thalassemia intermedia phenotype in the subject.
  Miyazaki et al. (1999) described compound heterozygosity for a
  beta(+)-thalassemia mutation and a new beta variant with low oxygen
  affinity, Hb Sagami (asn139 to thr).
  Henthorn et al. (1999) reported a new beta-globin variant, phe118 to
  cys, found in a newborn male of Indian Gujerati origin, living in the
  Harrow area of London, England. This variant was observed during a
  systematic program of neonatal screening. The mother also carried the
  abnormal hemoglobin.
  Wajcman et al. (1999) described a beta-globin variant in a 36-year-old
  French Caucasian male who presented with polycythemia. The variant was
  named Hb Brie Comte Robert for the place where the carrier resided. It
  was shown to have high oxygen affinity.
  In several members of a French family, Kister et al. (1999) identified a
  lys144-to-met mutation in the HBB gene. The mutation is a clinically
  silent variant in which the structural modification disturbs the
  oxygen-linked chloride binding.
  In 3 members of a family from Bologna, Italy, Ivaldi et al. (1999)
  demonstrated that erythrocytosis was the result of a variant beta-globin
  chain, a CAC-to-TAC mutation in codon 146 leading to a his146-to-tyr
  amino acid substitution. Ivaldi et al. (1999) pointed out that this was
  the sixth substitution that had been identified in the C-terminal
  residue of the beta-globin chain, the others being his146-to-asp
  (141900.0110), his146-to-pro (141900.0305), his146-to-leu (141900.0056),
  his146-to-arg (141900.0051), and his146-to-gln (141900.0409).
  Gilbert et al. (2000) described a second case of Hb Bologna-St. Orsola
  in a family of Anglo-Celtic origin.
  In a 15-year-old Portuguese girl with erythrocytosis, Bento et al.
  (2000) found a new high oxygen affinity variant called Hb Vila Real and
  characterized by a pro36-to-his (P36H) missense mutation of the HBB
  gene. The patient's mother had undergone regular phlebotomies over the
  previous 20 years for polycythemia, with an obstetric history of 2
  miscarriages, a stillborn baby, and 2 normal children by elective
  Cesarean section. A transversion converted codon 36 from CCT to CAT. The
  variant was named after the city in Portugal where the carrier was born.
  Salzano et al. (2002) reported the same rare high oxygen affinity
  hemoglobin variant in a 22-year-old male patient from Naples, Italy,
  affected by erythrocytosis. The DNA mutation was identified as a change
  in codon 36 of the HBB gene from CCT to CAT. The father carried the same
  hemoglobin variant in heterozygous state.
  In a 3-year-old anemic German girl, Bisse et al. (2000) detected an
  abnormal hemoglobin by cation-exchange high performance liquid
  chromatography. Further studies characterized the variant as a
  thr84-to-ala replacement in the HBB gene, which the authors named Hb
  Saale for the river crossing the city in which the proband lived. Hb
  Saale could be not be separated by electrophoresis or isoelectric
  focusing. It was found to be slightly unstable, exhibiting a moderate
  tendency to autooxidize. Functional properties and the heterotropic
  interactions were similar to those of hemoglobin A.
  Wajcman et al. (2000) found a hemoglobin variant, designated Hb Bushey,
  in a Chinese baby and his father. The variant was found to be caused by
  a point mutation leading to a phe122-to-leu substitution in the HBB
  gene. The same amino acid substitution was found in Hb Casablanca
  (141900.0493), in combination with another abnormality in the HBB gene,
  i.e., a lys65-to-met amino acid substitution (Hb J (Antakya);
  Wajcman et al. (2000) found a hemoglobin variant in a family in Morocco
  and designated it Hb Casablanca. It was found to be another example of a
  hemoglobin variant with 2 abnormalities in the same chain: the first was
  identical to that of Hb Bushey (phe122 to leu; 141900.0492) and the
  second to that of Hb J (Antakya) (lys65 to met; 141900.0121). The
  stability and oxygen-binding properties of Hb Bushey and Hb Casablanca
  were identical to those of Hb A.
  Oribe et al. (2000) found a new hemoglobin variant in a Japanese male: a
  change at codon 117 of the HBB gene from CAC (his) to TAC (tyr). The
  authors designated this variant Hb Tsukumi after the patient's place of
  residence. Two other hemoglobin variants have a change in his117: a
  change to arg in the case of Hb P (Galveston) (141900.0213), and a
  change to pro in the case of Hb Saitama (141900.0250).
  North et al. (2001) found Hb Tsukumi in a Moroccan woman.
  Analysis of globin chains by reversed phase high performance liquid
  chromatography, used as an additional tool for characterizing hemoglobin
  variants, led to the discovery of a new class of variants that display
  only differences in hydrophobicity. Groff et al. (2000) described 2 such
  variants: Hb Ernz and Hb Renert (141900.0496). Hb Ernz, a thr123-to-asn
  substitution, was found in a man of Italian origin who was polycythemic
  and in 2 of his 3 daughters who were hematologically normal. See
  141900.0294 for a thr123-to-ile substitution.
  Groff et al. (2000) identified Hb Renert, a val133-to-ala substitution
  in the HBB gene, in a man from Cape Verde who also carried Hb S
  (141900.0243) and presented with chronic hemolysis.
  Wilson et al. (2001) described a second case of Hb Renert. They
  commented that this was only the second hemoglobin variant involving
  beta-133, the other being Hb Extremadura (V1133L; 141900.0074).
  Four hemoglobin variants had previously been described that involve the
  first codon of the HBB gene: Hb Doha (141900.0069), Hb South Florida
  (141900.0266), Hb Niigata (141900.0471), and Hb Raleigh (141900.0233).
  Although none of these variants cause any significant clinical problems,
  mutations of the first codon are of interest because of their potential
  interference with cotranslational modification at this site during
  beta-globin synthesis. In eukaryotes, the translation of all peptide
  mRNAs starts at an AUG codon, producing methionine at the beginning of
  the nascent peptide chain. In most proteins, including alpha-, beta-,
  and gamma-globin, this methionine is cotranslationally cleaved when the
  chain is 20 to 30 amino acids long. This results in the first amino acid
  being valine in alpha-, beta-, and delta-globin, and glycine in
  gamma-globin. When the peptide chain is 40 to 50 amino acids long,
  further modification occurs with acetylation at the NH2-terminal
  residue. The extent of the acetylation depends on the identity of the
  N-terminal amino acid; valine is strongly inhibitory to this process,
  leading to little acetylation of alpha- and beta-globin. However, the
  N-terminal glycine of gamma-globin is less inhibitory, resulting in
  about 15% acetylation. Fisher et al. (2000) identified a new Hb variant,
  Hb Watford, in which a GTG-to-GGG substitution caused a change of the
  first amino acid of the beta-globin chain from methionine to glycine,
  mimicking the gamma-globin chain. The proband was a 48-year-old female
  of Jewish extraction who was evaluated for chronic mild anemia. Another
  mutation was found in cis with the val1-to-gly mutation: Cap+36G-A.
  Yapo et al. (2001) described a val134-to-ala missense mutation of the
  HBB gene in a 45-year-old man originating from Cameroon, a migrant
  worker in France. He was a compound heterozygote for this mutation,
  designated Hb Yaounde, and for Hb Kenitra (141900.0147). Hb Kenitra had
  previously been described only in persons of Moroccan origin. Hb Yaounde
  appeared to be neutral; Hb Kenitra is associated with expression at a
  level slightly higher than that of Hb A.
  Faustino et al. (2004) described Hb Yaounde in a 3-generation Portuguese
  family. The proband had compound heterozygosity for this hemoglobin
  variant and for hemoglobin C (glu6 to lys; 141900.0038). Hb Yaounde was
  associated with the Mediterranean haplotype II, supporting the
  hypothesis of a genetic origin independent of the African origin.
  Papassotiriou et al. (2001) identified hemoglobin Sitia, an
  ala128-to-val missense mutation in the HBB gene, in a Greek female with
  slightly reduced red blood cell indices.
  In a 33-year-old French Caucasian woman displaying a well-tolerated
  chronic anemia, Wajcman et al. (2001) found Hb Mont Saint-Aignan, a
  mildly unstable variant associated with hemolytic anemia, marked
  microcytosis, and increased alpha/beta biosynthetic ratio. The molecular
  defect was an ala128-to-pro missense mutation of the HBB gene.
  In a Dutch patient of Chinese origin, Harteveld et al. (2001) identified
  a new hemoglobin variant, Hb 't Lange Land, caused by a GGT-to-CGT
  transversion at codon 136 in exon 3 of the HBB gene, predicted to result
  in a gly136-to-arg (G136R) substitution. The authors stated that 3
  mutations inducing a single amino acid substitution at codon 136 were
  known: Hb Hope (gly136 to asp; 141900.0112), and 2 others based on
  personal communication from H. Wajcman, Hb Petit Bourg (gly136 to ala)
  and Hb Perpignan (gly136 to ser).
  In an asymptomatic Indian male belonging to the Agri caste group and
  originating from Mumbai in Maharashtra State, India, Colah et al. (2001)
  found a new hemoglobin variant, Hb D (Agri), with 2 amino acid
  substitutions in the same beta chain: glu121 to gln (141900.0065) and
  ser9 to tyr.
  Keser et al. (2001) identified a 9-bp (TCTGACTCT) deletion/insertion at
  codons 3-5 of the HBB gene in a 26-year-old woman with beta-thalassemia
  trait. The change was found to be the result of a deletion of cytosine
  (-C) at codon 5 (1 of the nucleotides in the thirteenth or fourteenth
  position of exon 1), and an insertion of thymine (+T) in front of codon
  3 at the tenth nucleotide in exon 1 of the HBB gene. As a result of
  these mutations, the amino acids at codons 3-5 were changed from
  leu-thr-pro to ser-asp-ser. This partial frameshift mutation led to a
  very unstable beta-globin chain.
  Kyrri et al. (2001) found a nonpathologic Hb variant in a Greek Cypriot
  male originating from Limassol, a town on the south coast of Cyprus. A
  G-to-C substitution in codon 8 (AAG to AAC) led to a lys8-to-asn (K8N)
  amino acid substitution. The 4 previously described amino acid
  substitutions at residue 8 of the beta-globin chain (lys8 to thr,
  141900.0237; lys8 to gln, 141900.0135; lys8 to glu, 141900.0191; and
  lys8 to met, 141900.0460), and the 2 hemoglobin variants with amino acid
  substitutions at the equivalent residue of the alpha-globin chain (lys7
  to asn, 141800.0187 and lys7 to glu, 141800.0192) are nonpathologic as
  Badens et al. (2002) described a 'new' mechanism leading to thalassemia
  intermedia, a moderate form of thalassemia: a somatic deletion of the
  HBB gene in the hemopoietic lineage of a heterozygous beta-thalassemic
  patient. The deletion occurred on the chromosome 11 inherited from the
  mother, who had no abnormality of the HBB gene. The father had a
  beta-thalassemic trait due to the Mediterranean HBB nonsense mutation
  (141900.0312). The deletion gave rise to a mosaic of cells with either 1
  or no functional beta-globin gene and it extended to a region of
  frequent loss of heterozygosity called LOH11A, which is located close to
  the HBB locus. Thus, loss of heterozygosity can be a cause of
  nonmalignant genetic disease.
  Brennan et al. (2002) found hemoglobin Canterbury by chance when a
  supposedly normal lysate was used as a control for an isopropanol
  stability test. The sample came from a 55-year-old man with Cowden
  disease due to a novel mutation in the PTEN gene (601728.0022), reported
  by Raizis et al. (2000). The isopropanol stability test showed a
  precipitate, suggesting a slightly unstable hemoglobin.
  Prehu et al. (2002) described a heterozygous hemoglobin variant that
  combined the change of Hb O-Arab (141900.0202) and Hb Hamilton
  (141900.0099) on the same HBB allele. The other allele carried the Hb S
  mutation (141900.0243). The patient was a child of Chad-Sudanese
  descent, suffering from a sickle cell syndrome. Compared to the classic
  description of the Hb S/Hb O-Arab association, the additional Hb
  Hamilton mutation did not seem to modify the clinical presentation.
  Qualtieri et al. (2002) identified a new neutral hemoglobin variant in a
  pregnant Italian woman that resulted from a GTG-to-CTG replacement at
  codon 126 of the HBB gene, corresponding to a val-to-leu amino acid
  change. Thermal and isopropanol stability tests were normal and there
  were no abnormal clinical features.
  HBB, 1-BP DEL 
  Waye et al. (2002) described a case of dominant beta-thalassemia in a
  38-year-old Canadian male of northern European extraction. He was anemic
  at birth and required periodic blood transfusions until about 2 years of
  age. Subsequently, he was under close medical supervision for his anemia
  and thrombocytosis, but did not require further transfusions. He had
  been asymptomatic throughout childhood. At age 20 years, he was found to
  have splenomegaly, and splenectomy was performed at age 23 because of
  mild symptoms and to prevent splenic rupture during karate competitions.
  After surgery he received Pneumovax, a prophylaxis against pneumococcal
  infections. He remained on folic acid supplementation, which had been
  started in childhood. The family history was negative for hematologic
  disorders. He was shown to have the normal complement of 4 alpha-globin
  genes. He was heterozygous for a single-nucleotide deletion in the HBB
  gene converting codon 113 from GTG to TG. This frameshift mutation was
  predicted to give rise to an extended beta chain of 156 amino acid
  residues. It was considered to be a de novo mutation. The mutation in
  this case most closely resembled that of Hb Geneva (141900.0335), an
  unstable beta-chain variant due to a complex rearrangement at codon 114.
  Both mutations give rise to extended beta chain variants of 156 amino
  acids differing only at residues 113 and 114 (cys-val for the codon 113
  mutation and val-gly for the codon 114 mutation). In both instances, it
  was not possible to detect even a trace of the predicted Hb variant in
  carriers of the mutation.
  Waye et al. (2002) stated that more than 30 dominant beta-thalassemia
  alleles had been reported.
  So et al. (2002) described a 35-year-old woman in whom a beta-chain
  variant was found on assay for Hb A(1c) performed because of impaired
  glucose tolerance during pregnancy. The raised hemoglobin level was
  suggestive of a hemoglobin variant with high oxygen affinity. The
  patient was heterozygous for a CAC-to-CAG transversion at codon 146,
  corresponding to a substitution of histidine by glutamine in the
  beta-globin chain. The same amino acid substitution at codon 146 occurs
  in the high oxygen affinity variant Hb Kodaira (141900.0409); however,
  Hb Kodaira resulted from a point mutation of CAC-to-CAA at codon 146.
  Not unexpectedly, the phenotypic manifestation of the 2 mutations was
  identical. This second form of his146 to gln (H146Q) was referred to as
  hemoglobin Kodaira II.
  Ngiwsara et al. (2003) described a case of Hb Kodaira II in Thailand.
  Prehu et al. (2002) described a novel unstable hemoglobin variant with
  low oxygen affinity and called it Hb Ilmenau for the city where the
  patient lived. The variant hemoglobin had a phe41-to-cys (F41C)
  substitution due to a TTC-to-TGC transversion in codon 41. The patient
  was a 29-year-old man who had suffered from anemia since childhood. When
  he was 4 years old, a nonspherocytic anemia was diagnosed with
  hepatosplenomegaly and cyanosis for which no cardiac origin could be
  found. He was splenectomized at the age of 8 years, without any
  significant clinical or biologic improvement.
  In a 32-year-old woman from Provence, southeast France, Lacan et al.
  (2002) found a novel unstable beta-chain variant with a GGC-GCC
  transversion resulting in a gly64-to-ala (G64A) substitution. The
  presence of Heinz bodies and reduced percentage (23 to 35%) of the
  abnormal hemoglobin fraction suggested a moderate instability in the
  hemoglobin, which the authors designated Hb Aubagne.
  Cobian et al. (2002) found Hb Colima, a ser49-to-cys change (S49C) of
  the beta-globin chain, in a 52-year-old Mestizo female who was born in
  Colima, Mexico. This was the second mutation at beta-49, the first being
  Hb Las Palmas (ser49 to phe), a slightly unstable variant (141900.0155).
  During a screening for hemoglobinopathies in blood donors in Brazil,
  Kimura et al. (2002) identified a beta-globin variant in a 30-year-old
  Caucasian woman of mixed Native Indian and Italian origin. The base
  substitution in codon 61 of the HBB gene from AAG to CAG caused a
  lys-to-gln (K61Q) change. This was the fourth description of a missense
  mutation at lys61 of the HBB gene: see Hb N-Seattle (K61E; 141900.0190),
  found in a black American blood donor; Hb Hikari (K61N; 141900.0106),
  found in a Japanese family; and Hb Bologna (K61M; 141900.0024), found in
  a northern Italian family. The missense mutations found at this position
  (external contacts of the Hb molecule) did not cause clinical
  manifestations; all the carriers described had been asymptomatic.
  HBB, 1-BP DEL, 144A
  In a 31-year-old woman from Trento in northeastern Italy, Ivaldi et al.
  (2003) found anomalous hemoglobin: an elongated C-terminal variant due
  to deletion of an A in codon 144. The deletion led to the replacement of
  lysine by serine at residue 144, the disappearance of the stop codon at
  position 147, and the presence of 12 additional residues, identical to
  those observed in hemoglobins Saverne (141900.0255), Tak (141900.0279),
  and Cranston (141900.0057), which result from a similar mechanism. Hb
  Trento, amounting to 29% of the total hemoglobin, was unstable and, like
  the other variants of this group, had an increased oxygen affinity. It
  led to a mild compensated hemolytic anemia with red cell inclusion
  In a 22-year-old Spanish male presenting with jaundice and suffering
  from hemolytic crises during infections, Villegas et al. (2003)
  identified an unstable Hb variant in which the valine residue at
  position 34 of the beta-globin chain was replaced by aspartic acid
  (val34 to asp; V34D).
  During glycohemoglobin determination by HPLC in a 76-year-old Japanese
  woman, Miyazaki et al. (2003) identified a homozygous change of codon
  138 of the HBB gene from GCT (ala) to ACT (thr) (A138T). No information
  on the clinical state of the patient was provided. In Hb Brockton
  (141900.0032), ala138 is changed to pro. Heinz body hemolytic anemia has
  been observed with that mutation.
  In a 6-month-old infant and in her mother of Mexican ancestry who lived
  in San Jose, California, Hoyer et al. (2003) identified a hemoglobin
  variant with abnormal oxygen affinity, designated Hb Santa Clara. A
  change of codon 97 of the HBB gene from CAC to AAC resulted in a
  his97-to-asn (H97N) change. Both the infant and her mother exhibited
  mild erythrocytosis.
  In a 29-year-old Caucasian woman who lived near Sparta, Michigan, Hoyer
  et al. (2003) identified a hemoglobin variant with high oxygen affinity,
  designated Hb Sparta. A smoker of 1 pack per day for 15 years, she was
  found to have mild erythrocytosis. A change of codon 103 of the HBB gene
  from TTC to GTC resulted in a phe103-to-val (F103V) change. Phe103 is
  replaced by leu in Hb Heathrow (141900.0102), and by ile in Hb Saint
  Nazaire (141900.0436); both variants are associated with erythrocytosis.
  Weatherall et al. (1973) described an Irish family with an unusual form
  of beta-thalassemia that was characterized by anemia, splenomegaly, and
  gross abnormalities of the erythrocytes and their precursors; the
  disorder was transmitted through several generations in an autosomal
  dominant fashion. Initially the disorder was labeled dyserythropoietic
  anemia, congenital, Irish or Weatherall type (603902). Thein et al.
  (1990) restudied the Irish family and 3 similarly affected kindreds, all
  of Anglo-Saxon origin, and pointed to similar cases reported by others
  and to the fact that the designation inclusion body beta-thalassemia had
  been proposed (Stamatoyannopoulos et al., 1974). All affected members of
  the original Irish family had a moderate anemia with splenomegaly,
  increased levels of Hb A2 and Hb F, and increased alpha/beta chain
  synthesis ratios. Two family members had undergone splenectomy. By the
  time of the report of Thein et al. (1990), 1 family member had died,
  showing at autopsy extensive extramedullary hemopoiesis and iron
  overload in parenchymal tissues in a pattern typical of excessive iron
  absorption rather than transfusion. The family had a complex
  rearrangement in the third exon of the HBB gene that involved 2
  deletions, 1 of 4 bp in codons 128 and 129 and the other of 11 bp in
  codons 132-135. The deletions were interrupted by an insertion of 5 bp,
  CCACA, followed by the normal sequence of 8 nucleotides. The
  modification resulted in a frameshift reading through to codon 153,
  predicting the synthesis of a variant beta-globin 7 residues longer than
  normal. Thein et al. (1990) suggested that the phenotypic difference
  between this condition and the more common recessive forms of
  beta-thalassemia lies mainly in the length and stability of the abnormal
  translation products that are synthesized and, in particular, whether
  they are capable of binding heme and producing aggregations that are
  relatively resistant to proteolytic degradation.
  Bundgaard et al. (2004) described a hemoglobin variant with 2 amino acid
  substitutions: Hb S, which is a glu6-to-val substitution (G6V;
  141900.0243), and Hb Agenogi, which is a glu90-to-lys substitution
  (G90K; 141900.0003). As the patient originated from Cameroon, the
  variant was designated Hb S (Cameroon). The authors stated that 4 double
  mutations on the same allele with the Hb S variant had previously been
  described: Hb S (Antilles) (141900.0244), Hb S (Providence)
  (141900.0246), Hb S (Oman) (141900.0245), and Hb S (Travis)
  In several members of a family from Naples, Italy, Pagano et al. (2004)
  identified a change of codon 86 of the HBB gene from GCC (ala) to CCC
  (pro) (A86P). The variant, which is unstable and has high oxygen
  affinity, was designated Hb Cardarelli. The A86P mutation had previously
  been found in the doubly substituted, unstable, and hyperaffine variant
  Hb Poissy (141900.0223), in which it occurs in combination with
  gly56-to-arg of Hb Hamadan (G56R; 141900.0098).
  Geva et al. (2004) described a girl of Puerto Rican descent who
  presented with symptomatic sickle cell disease exacerbated by mild
  hypoxemia, despite a newborn screening diagnosis of sickle cell trait.
  The child was found to be heterozygous for mutations in the HBB gene:
  the sickle cell mutation glu6 to val (G6V; 141900.0243), and a neutral
  leu68-to-phe (L68F; 141900.0524) mutation. Analysis of the patient's
  hemoglobin demonstrated that the doubly mutant protein, which the
  authors called hemoglobin Jamaica Plain (Hb JP) for Jamaica Plain,
  Massachusetts, had severely reduced oxygen affinity, especially in the
  presence of 2,3-diphosphoglycerate. Structural modeling suggested
  destabilization of the oxy conformation as a molecular mechanism for
  sickling in a heterozygote at an ambient partial pressure of oxygen. The
  patient's sickle cell disease was exacerbated by intercurrent
  respiratory infection, and she developed splenomegaly. The splenomegaly
  and anemia were recurrent. At the age of 19 months, during her first
  airplane trip, the child became acutely ill, with her spleen reaching
  the pelvic brim, as reported by a physician on board. After landing, she
  was hospitalized and found to have a hematocrit of 18%. Packed red cells
  were transfused; the hematocrit then rose to 28% with resolution of
  symptoms and a decrease in splenomegaly. Because of the apparent splenic
  sequestration crisis, a splenectomy was performed when she was 2 years
  old. Since that time, she had been asymptomatic and required no
  transfusions in the previous 24 months. In a commentary on the work of
  Geva et al. (2004), Benz (2004) noted that by itself, the L68F mutation
  is known as hemoglobin Rockford, a member of a class of 'low affinity
  hemoglobins' with reduced affinity for oxygen. These hemoglobins cause
  few symptoms, if any. When the L68F and G6V mutations coexist in the
  same beta-globin molecule, the L68F mutation causes Hb JP to desaturate
  easily and therefore to sickle more readily than ordinarily occurs with
  Hb S (G6V).
  Perrault et al. (1997) described a low-affinity, stable hemoglobin
  variant that did not result in hemolysis, which they designated Hb
  Rockford; the variant is caused by a 335C-T transition in the HBB gene,
  resulting in a leu68-to-phe (L68F) substitution. Geva et al. (2004)
  described a hemoglobin variant with 2 amino acid substitutions, Hb
  Rockford and Hb S (G6V; 141900.0243), which they designated Hb Jamaica
  Plain (141900.0523).
  In a 5-year-old boy of Libyan origin living in Tripoli, Libya, Lacan et
  al. (2004) identified a change of codon 26 of the HBB gene from GAG
  (glu) to GCG (ala) (glu26 to ala). They designated this hemoglobin
  variant Hb Tripoli.
  In a 66-year-old man born in Tizi-Ouzou in northeastern Algeria, Lacan
  et al. (2004) described abnormal hemoglobin with change of codon 29 in
  the first exon of the HBB gene from GGC (gly) to AGC (ser) (gly29 to
  ser). The carrier showed hematologic abnormalities; the presence of
  microcytosis and hypochromia was explained by an additional homozygous
  3.7 kb alpha(+)-thalassemic deletion.
  HBB, 3-UNT, T-A, +3 
  In a Tunisian patient with thalassemia intermedia, Jacquette et al.
  (2004) identified compound heterozygosity for mutations in the HBB gene:
  a change from AATAAA to AAAAAA in the polyadenylation site of the gene
  and a 2-bp insertion (25insTA) in codon 9 (141900.0528), causing a
  frameshift with a premature termination at codon 19.
  HBB, 2-BP INS, 25TA
  See 141900.0527 and Jacquette et al. (2004).
  HBB, 1-BP DEL, C
  In 4 members of a Mexican family, Perea et al. (2004) identified
  heterozygosity for a 1-bp deletion (a cytosine) in the HBB gene,
  resulting in a frameshift. The 1-bp deletion was either in codon 77,
  changing CAC (his) to CA, or in codon 78, changing CTG (leu) to TG.
  HBB, -101C-T 
  The expression 'silent beta-thalassemia' is used to indicate a group of
  thalassemia mutations that, in the heterozygous state, are characterized
  by normal hematologic indices, normal or borderline HbA2 (141850) and
  HbF levels, and a slight imbalance of beta-globin chain synthesis
  (Weatherall and Clegg, 2001). These mutations are usually identified by
  genetic and molecular analysis of families in which a proband is
  affected by thalassemia intermedia resulting from a compound
  heterozygous state for a typical beta-thalassemia and silent
  beta-thalassemia. One of the most common silent beta-thalassemia
  mutations, described in several Mediterranean populations, is the C-to-T
  substitution at position -101 in the distal CACCC box (141900.0370),
  which leads to a moderate reduction of the expression level of the
  beta-globin gene. In a silent beta-thalassemia carrier of Ashkenazi
  Jewish descent, Moi et al. (2004) identified a C-to-G transversion at
  the -101 position within the distal CACCC box of the HBB gene.
  During the assay of Hb A(1c) in a diabetic patient, Nakanishi et al.
  (1998) identified a beta-chain variant: a change of codon 52 in exon 2
  of the HBB gene from asp (GAT) to gly (GGT) (asp52 to gly). The patient
  was hematologically normal.
  In a 53-year-old Japanese woman who underwent routine Hb A(1c) assay,
  Miyazaki et al. (2005) identified 2 mutations in the same HBB gene:
  codon 141 was changed from CTG (leu) to GTG (val) (L141V), and codon 144
  was changed from AAG (lys) to TAG (stop) (K144X), leading to deletion of
  the last 3 amino acids of the beta-globin chain, lys-tyr-his. The
  increased oxygen affinity of the hemoglobin was consistent with the
  presence of mild erythrocytosis.
  In a 77-year-old Dutch woman with erythrocytosis, Harteveld et al.
  (2005) identified heterozygosity for a GTT-to-GCT transition at codon 23
  of the HBB gene, causing a valine-to-alanine (V23A) amino acid change.
  This was the fourth single-nucleotide substitution at codon 23 of the
  HBB gene and the second that was associated with erythrocytosis.
  In a 69-year-old man, Lacan et al. (2005) identified a TCT-to-TAT
  transversion in codon 9 of the HBB gene, resulting in a ser9-to-tyr
  (S9Y) amino acid change. No hematologic abnormalities were found. The
  patient lived in the town of Brem-sur-Mer on the Atlantic coast of
  Harteveld et al. (2005) observed an abnormal hemoglobin fraction during
  an HPLC assay for Hb A(1c) control for diabetes mellitus in a
  56-year-old northern European woman. This same abnormal fraction was
  found in 3 of her 5 sibs and in her son. There was no history of anemia,
  hemolytic, or circulatory episodes. Direct sequencing of the HBB gene
  revealed a GAC-to-TAC transversion in heterozygous form at codon 94.
  They concluded that the variant is a stable hemoglobin associated with a
  slightly elevated oxygen affinity. Harteveld et al. (2005) noted that
  this was the fourth mutation known to involve the asp94 residue of the
  HBB gene; see 141900.0016, 141900.0035, and 141900.0045. A frameshift
  mutation has also been reported at this position (141900.0338).
  In a 3-generation family from western Sicily, Giambona et al. (2006)
  identified heterozygosity for a GCC-GTC transition in the HBB gene,
  resulting in an ala70-to-val (A70V) substitution. Three mutations at
  codon 70 of the HBB gene had been previously described, all presenting
  with hemolytic anemia. In the new case, no anemia or other alteration of
  hematologic indices was found. The family lived in the town of Marineo
  near Palermo, Sicily.
  Ropero et al. (2006) described Hb La Coruna, a novel hemoglobin variant
  with increased oxygen affinity, leading to erythrocytosis. It is an
  electrophoretically silent variant that can be detected by
  reversed-phase high performance liquid chromatography (HPLC) and
  characterized by DNA sequencing. The patient was a 22-year-old Spanish
  male whose family lived in La Coruna in the northwest of Spain. The
  mother was also a carrier.
  HEMOGLOBIN CASERTA. Beta chain anomaly. See Ventruto et al. (1965) and
  Quattrin et al. (1970).
  HEMOGLOBIN D (FRANKFURT). Beta chain anomaly. See Martin et al. (1960)
  and Gammack et al. (1961).
  HEMOGLOBIN DURHAM-I (HEMOGLOBIN R). Beta chain anomaly. See Chernoff and
  Weichselbaum (1958) and Chernoff and Pettit (1964).
  HEMOGLOBIN J (JAMAICA). Beta chain anomaly. See Gammack et al. (1961).
  HEMOGLOBIN K. Beta chain anomaly. See O'Gorman et al. (1963).
  HEMOGLOBIN KINGS COUNTY. Probably beta chain defect. Observed in an
  American black family. Affected persons had nonspherocytic hemolytic
  Heinz body anemia. See Sathiapalan and Robinson (1968).
  HEMOGLOBIN L. Beta chain anomaly. See Ager and Lehmann (1957) and
  Gammack et al. (1961).
See Also:
  Antonarakis et al. (1984); Antonarakis et al. (1982); Arous et al.
  (1982); Bank et al. (1980); Barwick et al. (1985); Bernards et al.
  (1979); Blackwell et al. (1971); Blackwell et al. (1972); Blackwell
  et al. (1970); Blackwell et al. (1972); Blackwell et al. (1969); Blackwell
  et al. (1970); Blackwell et al. (1969); Blackwell et al. (1969); Blouquit
  et al. (1984); Boyer et al. (1963); Brennan et al. (1977); Cai et
  al. (1989); Cai Yin Lin et al. (1982); Cao et al. (1981); Chang et
  al. (1983); Chang and Kan (1982); Chang and Kan (1979); Charache et
  al. (1977); Chen et al. (1985); Chifu et al. (1992); Cole-Strauss
  et al. (1996); Driscoll et al. (1981); Edison et al. (2005); Efstratiadis
  et al. (1980); Enver et al. (1990); Forget  (1979); Fritsch et al.
  (1980); Gacon et al. (1977); Garel et al. (1976); Gilbert et al. (2000);
  Gonzalez-Redondo et al. (1989); Gusella et al. (1979); Harano et al.
  (1985); Harano et al. (1990); Harano et al. (1991); Harano et al.
  (1990); Harano et al. (1990); Harano et al. (1983); Harano et al.
  (1981); Hebbel et al. (1977); Heller et al. (1966); Honig et al. (1990);
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  beta-87 (F3) deleted and hemoglobin St. Antoine: gly-to-leu beta-74-75
  (E18-19) deleted: consequences for oxygen affinity and protein stability. Biochi  m.
  Biophys. Acta 295: 495-504, 1973.
  1138. Wajcman, H.; Lahary, A.; Prome, D.; Kister, J.; Riou, J.; Godart,
  C.; Prehu, C.; Traeger-Synodinos, J.; Papassotiriou, I.; Galacteros,
  F.: Hb Mont Saint Aignan (beta-128(H6)ala-to-pro): a new unstable
  variant leading to chronic microcytic anemia. Hemoglobin 25: 57-65,
  1139. Wajcman, H.; Mrad, A.; Blouquit, Y.; Parmentier, C.; Riou, J.;
  Galacteros, F.: Hemoglobin Villejuif (beta123(H1)thr-to-ile): a new
  variant found in coincidence with polycythemia vera. Am. J. Hemat. 32:
  294-297, 1989.
  1140. Wajcman, H.; Riou, J.; Prome, D.; Kister, J.; Galacteros, F.
  : Hb Brie Comte Robert (beta-36(C2)pro-to-ala): a new hemoglobin variant
  with high oxygen affinity and marked hydrophobic properties. Hemoglobin 23:
  281-286, 1999.
  1141. Wajcman, H.; Vasseur, C.; Blouquit, Y.; Santo, D. E.; Peres,
  M. J.; Martins, M. C.; Poyart, C.; Galacteros, F.: Hemoglobin Redondo
  [beta 92(F8) his-to-asn]: an unstable hemoglobin variant associated
  with heme loss which occurs in two forms. Am. J. Hemat. 38: 194-200,
  1142. Walker, L.; McFarlane, A.; Patterson, M.; Eng, B.; Waye, J.
  S.: Hb Castilla [beta-32(B14)leu-to-arg] caused by a de novo mutation. Hemoglobi  n 27:
  253-256, 2003.
  1143. Watson-Williams, E. J.; Beale, D.; Irvine, D.; Lehmann, H.:
  A new haemoglobin, D Ibadan (beta-87 threonine-to-lysine), producing
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  1273-1279, 1965.
  1144. Waye, J. S.; Eng, B.; Patterson, M.; Chui, D. H. K.; Fernandes,
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  1150. Weatherall, D. J.; Clegg, J. B.; Collender, S. T.; Wells, R.
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  1169. Williamson, D.; Nutkins, J.; Rosthoj, S.; Brennan, S. O.; Williams,
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  269-278, 1991.
  1177. Wilson, J. B.; Webber, B. B.; Hu, H.; Kutlar, A.; Kutlar, F.;
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  Use of restriction endonucleases for mapping the allele for beta-S-globin. Proc.  
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  tyr-to-term), a human 'nonsense' mutation leading to a shortened beta
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  DNA. Nature 330: 384-386, 1987.
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  gel electrophoresis. Am. J. Hemat. 16: 47-52, 1984.
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  a high-oxygen-affinity variant causing erythrocytosis and forming
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  Hb J Georgia = Hb J Baltimore = beta16 gly-to-asp. Clin. Chim. Acta 35:
  521-522, 1971.
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  of strong selection around the HbC, a recently arisen mutation providing
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  in hemoglobin San Francisco. Clin. Res. 18: 134, 1970.
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  Punjab beta(0) thalassaemia in an English family with 22 cases of
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  Genet. 22: 377-381, 1985.
  1193. Yamada, H.; Hotta, H.; Ohba, Y.; Miyaji, T.; Ito, J.; Minami,
  M.: Hemoglobin Pyrgos (beta 83 gly-to-asp) in a Japanese family. Hemoglobin 1:
  245-256, 1977.
  1194. Yamagishi, Y.; Ikeda, K.; Takahara, J.; Irino, S.; Hasui, H.;
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  found in a Japanese family. Hemoglobin 17: 379-385, 1993.
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  characterization of beta-globin gene mutations in Malay patients with
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  variant found in association with Hb Kenitra (beta-69(E13)gly-to-arg)
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  found in China. Brit. J. Haemat. 67: 221-223, 1987.
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  in two Italian males. Hemoglobin 14: 459-461, 1990.
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Clinical Synopsis:
     Beta polypeptide hemoglobin chain;
     Congenital dyserythropoietic anemia (Irish type);
     Mild hemolytic anemia (e.g. Hb Extremadura 141900.0074);
     Hemolytic microcytic anemia in compound heterozygosity with Hb C (e.g.
     Hb Korle-bu 141900.0153);
     Macrocytic hemolytic disease (e.g. Hb Redondo 141900.0404);
     Erythrocytosis (e.g. Hb Brigham 141900.0028);
     Congenital Heinz body anemia (e.g. Hb Bruxelles 141900.0033);
     Sickle cell anemia (homozygous Hb SS 141900.0243);
     Painful crises;
     Aplastic crises;
     Acute splenic sequestration;
     Avascular necrosis;
     Leg ulcers;
     Drug-induced hemolysis (e.g. Hb Zurich 141900.0310) Methemoglobinemia
     (e.g., HbM Saskatoon 141900.0165) Erythremia (e.g., Hb Osler 141900.0211)
     Cyanosis (e.g. Hb M Saskatoon 141900.0165)
     Splenomegaly (e.g. Hb Jacksonville 141900.0401);
     Splenic syndrome (e.g. Hb S 141900.0243)
     Hematuria (e.g. Hb Sarrebourg 141900.0435);
     Urine concentrating defect (e.g. Hb S 141900.0243)
     Resistance to falciparum malaria (e.g. Hb S. 141900.0243);
     Beta-delta fusion variant (e.g. Hb Lincoln Park 141900.0157);
     Abnormal red cell morphology;
     Bone marrow erythroid hyperplasia;
     Increased numbers of multinucleate red cell precursors;
     Inclusion bodies in normoblasts;
     Altered hemoglobin A(2) levels;
     Altered hemoglobin F levels;
     Unstable hemoglobin (e.g. Hb Koln 141900.0151);
     Diminished oxygen affinity (e.g. Hb Chico 141900.0048);
     Increased oxygen affinity (e.g. Hb Heathrow 141900.0102);
     Increased N-terminal glycation (e.g. Hb Himeji 141900.0107);
     Discrepant Hb A1c measurement (e.g. Hb Marseille 141900.0171);
     Unusually low Hb A(1c) level (e.g. Hb Kodaira 141900.0409);
     Red cell inclusion bodies (e.g. Hb Matera 141900.0173);
     Red cell sickling (e.g. Hb S 141900.0243);
     Non-Hb S red cell sickling (e.g. Hb C (Georgetown) 141900.0039);
     Electrophoretic migration as Hb S (e.g. Hb Muskegon 141900.0432);
     Increased red cell sickling tendency (e.g. Hb S (OMAN) 141900.0245)
     Autosomal dominant for some such as methemoglobinemia, polycythemia,
     and Heinz body hemolytic anemia;
     Autosomal recessive for others such as sickle cell disease and thalassemia
  Victor A. McKusick - updated: 11/25/1998
Edit Dates: 
  joanna: 11/25/1998
  Ada Hamosh - updated: 9/29/2010
  Paul J. Converse - updated: 5/14/2010
  Patricia A. Hartz - updated: 1/28/2010
  Paul J. Converse - updated: 11/11/2009
  Carol A. Bocchini - updated: 5/22/2009
  Paul J. Converse - updated: 3/13/2008
  Cassandra L. Kniffin - updated: 2/20/2008
  George E. Tiller - updated: 1/3/2008
  Matthew B. Gross - updated: 7/5/2007
  Victor A. McKusick - updated: 2/26/2007
  Victor A. McKusick - updated: 11/21/2006
  Victor A. McKusick - updated: 10/19/2006
  Victor A. McKusick - updated: 9/19/2006
  Victor A. McKusick - updated: 3/29/2006
  George E. Tiller - updated: 2/17/2006
  Victor A. McKusick - updated: 1/30/2006
  George E. Tiller - updated: 1/23/2006
  Victor A. McKusick - updated: 10/10/2005
  Victor A. McKusick - updated: 10/3/2005
  Victor A. McKusick - updated: 8/11/2005
  Ada Hamosh - updated: 7/27/2005
  Victor A. McKusick - updated: 6/20/2005
  Victor A. McKusick - updated: 5/11/2005
  Victor A. McKusick - updated: 3/7/2005
  Victor A. McKusick - updated: 3/3/2005
  Ada Hamosh - updated: 2/1/2005
  Victor A. McKusick - updated: 12/9/2004
  Victor A. McKusick - updated: 12/6/2004
  Victor A. McKusick - updated: 10/26/2004
  John A. Phillips, III - updated: 9/24/2004
  Victor A. McKusick - updated: 9/21/2004
  Victor A. McKusick - updated: 8/6/2004
  Victor A. McKusick - updated: 6/2/2004
  Victor A. McKusick - updated: 2/2/2004
  Victor A. McKusick - updated: 1/20/2004
  Victor A. McKusick - updated: 1/15/2004
  Victor A. McKusick - updated: 4/17/2003
  Victor A. McKusick - updated: 3/4/2003
  Victor A. McKusick - updated: 3/3/2003
  Victor A. McKusick - updated: 11/19/2002
  Victor A. McKusick - updated: 10/2/2002
  Victor A. McKusick - updated: 9/27/2002
  Victor A. McKusick - updated: 9/16/2002
  Victor A. McKusick - updated: 8/15/2002
  Victor A. McKusick - updated: 6/3/2002
  Victor A. McKusick - updated: 5/31/2002
  Victor A. McKusick - updated: 5/23/2002
  Victor A. McKusick - updated: 4/18/2002
  Victor A. McKusick - updated: 4/16/2002
  Victor A. McKusick - updated: 4/4/2002
  Victor A. McKusick - updated: 2/27/2002
  Victor A. McKusick - updated: 1/22/2002
  Ada Hamosh - updated: 11/15/2001
  Victor A. McKusick - updated: 11/2/2001
  Victor A. McKusick - updated: 11/1/2001
  Victor A. McKusick - updated: 10/10/2001
  Victor A. McKusick - updated: 2/28/2001
  Victor A. McKusick - updated: 2/14/2001
  Victor A. McKusick - updated: 11/3/2000
  Ada Hamosh - updated: 10/19/2000
  Victor A. McKusick - updated: 8/31/2000
  Victor A. McKusick - updated: 8/16/2000
  Victor A. McKusick - updated: 7/21/2000
  George E. Tiller - updated: 5/2/2000
  Victor A. McKusick - updated: 4/26/2000
  Victor A. McKusick - updated: 4/11/2000
  Victor A. McKusick - updated: 1/21/2000
  Victor A. McKusick - updated: 1/18/2000
  Carol A. Bocchini - updated: 12/14/1999
  Victor A. McKusick - updated: 12/8/1999
  Victor A. McKusick - updated: 9/15/1999
  Matthew B. Gross - updated: 8/26/1999
  Victor A. McKusick - updated: 8/25/1999
  Victor A. McKusick - updated: 8/13/1999
  Wilson H. Y. Lo - updated: 8/12/1999
  Victor A. McKusick - updated: 7/20/1999
  Ada Hamosh - updated: 6/27/1999
  Victor A. McKusick - updated: 5/24/1999
  Victor A. McKusick - updated: 12/21/1998
  Stylianos E. Antonarakis - updated: 12/13/1998
  Victor A. McKusick - updated: 11/19/1998
  Victor A. McKusick - updated: 8/26/1998
  Victor A. McKusick - edited: 8/19/1998
  Victor A. McKusick - updated: 4/30/1998
  Victor A. McKusick - updated: 3/31/1998
  Victor A. McKusick - updated: 2/17/1998
  Victor A. McKusick - updated: 11/5/1997
  Victor A. McKusick - updated: 9/29/1997
  Victor A. McKusick - updated: 9/11/1997
  Victor A. McKusick - updated: 8/13/1997
  Victor A. McKusick - updated: 5/28/1997
  Victor A. McKusick - updated: 2/28/1997
  Victor A. McKusick - edited: 2/21/1997
  Iosif W. Lurie - updated: 1/17/1997
  Moyra Smith - updated: 9/5/1996
  Moyra Smith - updated: 8/15/1996
  Orest Hurko - updated: 6/13/1995
Creation Date: 
  Victor A. McKusick: 6/24/1986
Edit Dates: 
  terry: 11/03/2010
  terry: 10/12/2010
  alopez: 10/5/2010
  terry: 9/29/2010
  carol: 8/5/2010
  mgross: 5/17/2010
  terry: 5/14/2010
  wwang: 3/26/2010
  alopez: 1/28/2010
  carol: 1/8/2010
  terry: 12/16/2009
  mgross: 12/1/2009
  terry: 11/11/2009
  wwang: 7/29/2009
  carol: 6/3/2009
  carol: 5/22/2009
  terry: 2/4/2009
  terry: 1/14/2009
  mgross: 3/19/2008
  terry: 3/13/2008
  wwang: 3/6/2008
  ckniffin: 2/20/2008
  wwang: 1/11/2008
  terry: 1/3/2008
  terry: 8/9/2007
  mgross: 7/5/2007
  alopez: 3/21/2007
  terry: 2/26/2007
  alopez: 11/27/2006
  terry: 11/21/2006
  alopez: 10/23/2006
  terry: 10/19/2006
  wwang: 10/3/2006
  terry: 9/19/2006
  terry: 6/23/2006
  alopez: 5/5/2006
  terry: 3/29/2006
  wwang: 3/2/2006
  terry: 2/17/2006
  alopez: 2/7/2006
  terry: 1/30/2006
  carol: 1/24/2006
  wwang: 1/23/2006
  carol: 1/19/2006
  alopez: 10/10/2005
  alopez: 10/7/2005
  terry: 10/3/2005
  carol: 10/3/2005
  terry: 9/27/2005
  wwang: 8/18/2005
  terry: 8/11/2005
  terry: 8/3/2005
  alopez: 7/28/2005
  terry: 7/27/2005
  carol: 7/19/2005
  alopez: 6/22/2005
  terry: 6/20/2005
  wwang: 6/7/2005
  wwang: 5/12/2005
  terry: 5/11/2005
  tkritzer: 3/11/2005
  terry: 3/7/2005
  terry: 3/4/2005
  terry: 3/3/2005
  tkritzer: 2/1/2005
  tkritzer: 1/25/2005
  terry: 12/9/2004
  terry: 12/6/2004
  terry: 11/3/2004
  tkritzer: 10/28/2004
  terry: 10/26/2004
  alopez: 9/24/2004
  tkritzer: 9/23/2004
  terry: 9/21/2004
  tkritzer: 8/10/2004
  terry: 8/6/2004
  tkritzer: 6/8/2004
  terry: 6/2/2004
  alopez: 5/27/2004
  terry: 5/20/2004
  tkritzer: 4/7/2004
  terry: 4/2/2004
  carol: 3/17/2004
  tkritzer: 2/2/2004
  terry: 2/2/2004
  tkritzer: 1/22/2004
  terry: 1/20/2004
  terry: 1/15/2004
  carol: 11/24/2003
  alopez: 11/14/2003
  alopez: 11/10/2003
  cwells: 11/7/2003
  carol: 8/25/2003
  terry: 7/30/2003
  carol: 5/13/2003
  tkritzer: 4/30/2003
  terry: 4/17/2003
  carol: 3/11/2003
  tkritzer: 3/7/2003
  terry: 3/4/2003
  terry: 3/3/2003
  tkritzer: 12/31/2002
  tkritzer: 11/27/2002
  tkritzer: 11/20/2002
  terry: 11/19/2002
  tkritzer: 10/7/2002
  tkritzer: 10/3/2002
  tkritzer: 10/2/2002
  carol: 9/27/2002
  carol: 9/16/2002
  tkritzer: 8/20/2002
  tkritzer: 8/16/2002
  terry: 8/15/2002
  carol: 7/29/2002
  alopez: 6/18/2002
  terry: 6/3/2002
  terry: 5/31/2002
  alopez: 5/28/2002
  terry: 5/23/2002
  cwells: 5/1/2002
  cwells: 4/24/2002
  terry: 4/18/2002
  terry: 4/16/2002
  cwells: 4/15/2002
  cwells: 4/10/2002
  terry: 4/4/2002
  cwells: 3/22/2002
  cwells: 3/20/2002
  terry: 2/27/2002
  terry: 2/8/2002
  carol: 2/5/2002
  mcapotos: 1/31/2002
  terry: 1/22/2002
  alopez: 11/15/2001
  terry: 11/15/2001
  carol: 11/8/2001
  mcapotos: 11/2/2001
  mcapotos: 11/1/2001
  carol: 10/12/2001
  terry: 10/10/2001
  terry: 2/28/2001
  carol: 2/26/2001
  terry: 2/26/2001
  carol: 2/20/2001
  mcapotos: 2/19/2001
  mcapotos: 2/16/2001
  terry: 2/14/2001
  mcapotos: 2/12/2001
  mcapotos: 1/12/2001
  mcapotos: 11/9/2000
  terry: 11/3/2000
  alopez: 10/19/2000
  terry: 9/15/2000
  terry: 8/31/2000
  carol: 8/29/2000
  terry: 8/16/2000
  alopez: 7/26/2000
  terry: 7/21/2000
  carol: 6/22/2000
  alopez: 5/2/2000
  mcapotos: 5/2/2000
  mcapotos: 4/28/2000
  mcapotos: 4/27/2000
  terry: 4/26/2000
  terry: 4/11/2000
  terry: 1/21/2000
  mcapotos: 1/20/2000
  mgross: 1/19/2000
  terry: 1/18/2000
  mcapotos: 12/15/1999
  carol: 12/14/1999
  carol: 12/9/1999
  terry: 12/8/1999
  carol: 10/5/1999
  mgross: 9/22/1999
  mgross: 9/21/1999
  terry: 9/15/1999
  carol: 9/8/1999
  carol: 8/26/1999
  mgross: 8/26/1999
  mgross: 8/25/1999
  mgross: 8/13/1999
  mgross: 8/12/1999
  jlewis: 8/5/1999
  terry: 7/20/1999
  kayiaros: 7/13/1999
  carol: 6/27/1999
  carol: 5/24/1999
  joanna: 5/20/1999
  carol: 12/29/1998
  terry: 12/21/1998
  carol: 12/13/1998
  carol: 11/25/1998
  terry: 11/19/1998
  joanna: 11/19/1998
  carol: 8/27/1998
  terry: 8/26/1998
  terry: 8/19/1998
  dkim: 7/24/1998
  dkim: 7/21/1998
  carol: 6/26/1998
  terry: 6/18/1998
  alopez: 6/9/1998
  dholmes: 6/8/1998
  alopez: 5/14/1998
  carol: 5/12/1998
  terry: 4/30/1998
  alopez: 3/31/1998
  terry: 3/24/1998
  mark: 3/2/1998
  terry: 2/17/1998
  jenny: 11/7/1997
  terry: 11/5/1997
  mark: 10/28/1997
  mark: 10/10/1997
  jenny: 10/1/1997
  terry: 9/29/1997
  terry: 9/26/1997
  dholmes: 9/26/1997
  dholmes: 9/19/1997
  jenny: 9/18/1997
  terry: 9/11/1997
  terry: 9/8/1997
  terry: 8/13/1997
  joanna: 8/12/1997
  terry: 8/6/1997
  alopez: 7/31/1997
  alopez: 7/28/1997
  terry: 7/10/1997
  alopez: 7/10/1997
  mark: 7/10/1997
  alopez: 7/10/1997
  mark: 7/8/1997
  terry: 7/7/1997
  jenny: 6/3/1997
  terry: 5/28/1997
  mark: 2/28/1997
  terry: 2/26/1997
  mark: 2/21/1997
  jamie: 1/17/1997
  jamie: 1/15/1997
  terry: 1/7/1997
  mark: 12/23/1996
  terry: 12/18/1996
  terry: 12/17/1996
  terry: 12/5/1996
  terry: 11/18/1996
  terry: 11/15/1996
  terry: 11/13/1996
  terry: 11/5/1996
  terry: 10/31/1996
  jamie: 10/30/1996
  mark: 9/11/1996
  mark: 9/5/1996
  terry: 9/5/1996
  marlene: 9/3/1996
  mark: 8/15/1996
  mark: 7/9/1996
  mark: 7/2/1996
  terry: 6/25/1996
  mark: 6/19/1996
  terry: 6/12/1996
  terry: 6/5/1996
  mark: 4/22/1996
  terry: 4/15/1996
  mark: 3/30/1996
  mark: 3/21/1996
  terry: 3/21/1996
  mark: 3/11/1996
  terry: 2/28/1996
  mark: 2/13/1996
  terry: 2/5/1996
  mark: 1/28/1996
  terry: 1/23/1996
  mark: 1/10/1996
  mark: 1/4/1996
  mark: 11/13/1995
  terry: 10/31/1995
  davew: 8/25/1994
  jason: 7/29/1994
  pfoster: 4/5/1994
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