MIM Entry: 141800
Title:
+141800 HEMOGLOBIN--ALPHA LOCUS 1; HBA1
;;3-PRIME @ALPHA-GLOBIN GENE;;
MINOR ALPHA-GLOBIN LOCUS
ALPHA-THALASSEMIAS, INCLUDED;;
METHEMOGLOBINEMIA, ALPHA-GLOBIN TYPE, INCLUDED;;
ERYTHREMIA, ALPHA-GLOBIN TYPE, INCLUDED
Text:
The alpha and beta loci determine the structure of the 2 types of
polypeptide chains in the tetrameric adult hemoglobin, Hb A,
alpha-2/beta-2. The alpha locus also determines a polypeptide chain, the
alpha chain, in fetal hemoglobin (alpha-2/gamma-2), in hemoglobin
A2(alpha-2/delta-2), and in embryonic hemoglobin (alpha-2/epsilon-2).
The number of normal alpha genes (3, 2, 1 or none) in Asian cases of
alpha-thalassemia results in 4 different alpha-thalassemia syndromes
(Kan et al., 1976). Three normal alpha genes gives a silent carrier
state. Two normal alpha genes results in microcytosis (so-called
heterozygous alpha-thalassemia). One normal alpha gene results in
microcytosis and hemolysis (so-called Hb H disease). No normal alpha
gene results in 'homozygous alpha-thalassemia' manifested as fatal
hydrops fetalis.
By studies of somatic cell hybrids, Deisseroth et al. (1976) showed that
the alpha and beta loci are on different chromosomes. Gandini et al.
(1977) concluded, incorrectly as it turned out, that the alpha loci are
on the long arm of chromosome 4 (4q28-q34). The conclusion was based on
a finding of excessive synthesis of alpha chains in patients with
duplication of this region. Deisseroth et al. (1977) combined the
methods of somatic cell hybridization and DNA-cDNA hybridization to
establish assignment of the alpha-globin locus to chromosome 16. This
represents an extension of the cell hybridization method permitting
mapping of genes that are not functional in the cultured cell. Weitkamp
et al. (1977) presented data concerning linkage of the alpha and beta
loci to 34 marker loci. Data on alpha-thalassemia, combined with those
on the Hopkins-2 variant, excluded linkage of alpha and haptoglobin at a
recombination fraction less than 0.15. Deisseroth and Hendrick (1978)
confirmed the assignment of the alpha locus to chromosome 16 by means of
cotransfer of this gene with the human APRT gene, known to be on 16 (see
102600), into mouse erythroleukemia cells. (The APRT gene is on the long
arm of chromosome 16.) On the basis of findings in a case of partial
trisomy 16, Wainscoat et al. (1981) concluded that the alpha-globin
genes are on segment 16pter-p12. By combining somatic cell hybridization
with a cDNA probe in the study of a cell line with reciprocal
translocation between 16q and 11q, Koeffler et al. (1981) showed that
the alpha-globin genes are on the short arm of 16. Gerhard et al. (1981)
used an improved method of in situ hybridization to confirm the
assignment of the alpha-globin cluster to chromosome 16p. The evidence
on the precise location of HBAC is conflicting, with assignments from
16p13.33 to 16p13.11 (Reeders, 1986). The fact that adult polycystic
kidney disease (APKD; 173900) is proximal to HBAC and is on the 5-prime
side of HBAC appears to indicate that the order is 16cen--APKD--5-prime
HBZ1--HBA1--3-prime HVR--pter. (3-prime HVR is the hypervariable region
used in mapping APKD to 16p.) On the basis of the findings in a fetus
with an unbalanced translocation involving 16p, Breuning et al. (1987)
concluded that the HBA cluster is distal to PGP. By a combination of in
situ hybridization, Southern blot analysis, and linkage analysis using
the fragile site 16p12.3 and translocation breakpoints within band
16p13.1, Simmers et al. (1987) mapped the alpha-globin gene complex to
16pter-p13.2. Buckle et al. (1988) described a child in whom cytogenetic
analysis indicated monosomy for 16pter-p13.3. DNA studies showed that
the patient had not inherited either maternal alpha-globin allele. The
child had the alpha-thalassemia trait as well as moderate mental
retardation and dysmorphic features. They determined that the gene is
located in the 16pter-p13.3 segment. After reviewing earlier data
placing the alpha-globin cluster slightly more proximal, they concluded
that the findings in this child may be more reliable.
Orkin (1978) identified alpha-globin gene fragments in restriction
endonuclease digests of total DNA after electrophoresis by hybridization
with P32-labeled cDNA probes. The data indicated that the alpha genes
occur in duplicate and that the 2 copies lie close together. Thus direct
physical evidence is provided for the duplication deduced from the
findings with mutant alpha chains and with the alpha-thalassemias and
the kinetics of hybridization in solution. The 2 alpha chains lie about
3.7 kilobases apart. Leder et al. (1978) presented evidence that the
alpha and beta genes of all adult mammalian hemoglobins have 2
intervening sequences at analogous positions. Wilson et al. (1977)
described a possible nucleotide polymorphism in the untranslated 3-prime
region of the alpha-globin gene and suggested that the heterogeneity is
related to the existence of 2 alpha gene loci. Musumeci et al. (1978)
pointed out that the combination of alpha-thalassemia and
beta-thalassemia leads to less severe clinical expression of homozygous
beta-thalassemia. The rarity of a chromosome 16 with both alpha loci
deleted (as demonstrated by the restriction endonuclease mapping
technique of Southern) explains the rarity of severe forms of
alpha-thalassemia in Africans, e.g., Hb H disease which requires loss of
3 alpha loci and homozygous alpha-thalassemia which requires loss of 4
alpha loci (Dozy et al., 1979). By restriction endonuclease mapping,
Goossens et al. (1980) identified 12 persons heterozygous for a
chromosome carrying 3 alpha genes. There were no hematologic
abnormalities. The frequency was 0.0036 in American Blacks and 0.05 in
Greek Cypriots. They had previously shown a frequency of 0.16 for the
single alpha-globin locus in black Americans. The single locus had a
frequency of 0.18 in Sardinians, but none of 125 Sardinians had a triple
alpha locus, suggesting that the former had a selective advantage. Greek
Cypriots have a frequency of 0.07 for the single alpha locus. Among 645
Japanese subjects studied, Nakashima et al. (1990) found 10 persons
heterozygous for a chromosome with the triplicated alpha-globin locus.
Thus, the frequency of the triplicate alpha locus was 0.008 in this
population, while that of the single alpha-locus, i.e., the
alpha-thalassemia-2 gene, may be lower than 0.0008. Analysis of
haplotypes suggested that the triple alpha loci may have had multiple
origins. Nakashima et al. (1990) commented on the fact that in Melanesia
the frequency of the triplicated genotype is about the same (Flint et
al., 1986) as in Japan, whereas the frequency of the single alpha gene
is much higher, compatible with a selective advantage vis-a-vis malaria.
Liebhaber et al. (1981) found identity of the alpha-1-globin genes from
an Asian and a Caucasian. Furthermore, the alpha-1 and alpha-2 genes
have a much higher degree of homology than would be predicted from the
timing of the duplication before the bird-mammal divergence (about 300
Myr ago). Liebhaber et al. (1981) presented this as evidence for the
existence of mechanisms for suppression of allelic polymorphisms and for
exchange of genetic information within the alpha-globin gene complex.
See 142200 for a discussion of gene conversion in relation to a
comparably surprising homology of the 2 gamma-globin genes.
Lehmann and Carrell (1984) suggested the use of the following
nomenclature for alpha-thalassemias based on the number of alpha-globin
genes that are missing or abnormal: 1-alpha-thalassemia (silent type);
2-alpha-thalassemia, trans or cis (thalassemia trait);
3-alpha-thalassemia (Hb H disease); and 4-alpha-thalassemia (Hb Bart's
hydrops fetalis). In this scheme, homozygous Hb Constant Spring is a
2-alpha-thalassemia which, if combined with a cis 2-alpha-thalassemia
heterozygous Hb Constant Spring, gives a 3-alpha-thalassemia and results
in Hb H disease. Lehmann and Carrell (1984) also proposed that the 2
alpha-globin genes be designated as 5-prime (now alpha-2) and 3-prime
(now alpha-1). Liebhaber and Cash (1985) described a method for
identifying whether the alpha-1 or alpha-2 locus is the site of
particular alpha-globin mutations. Rubin and Kan (1985) described a
sensitive method for determining how many alpha-globin genes are
present. It had the advantages of not requiring restriction enzyme
digestion and gel electrophoresis and using the much more stable isotope
(35)S rather than 32(P) for labeling. Only a small sample of DNA is
needed. Application of the approach to diagnosis of Down syndrome was
proposed. Assum et al. (1985) added a fourth restriction site
polymorphism in the alpha-globin gene cluster. Compared to the
beta-globin cluster, the alpha-globin cluster seemed to show a poverty
of DNA polymorphism; however, Higgs et al. (1986) demonstrated a
remarkable degree of DNA polymorphism in the alpha-globin gene cluster.
In addition, the RFLP haplotype is associated with hypervariable regions
of DNA.
Pseudo-alpha-1 (HBAP1), a pseudogene, is defective in several respects,
including splice junction mutations and premature termination codons.
Hardison et al. (1986) identified a previously undetected pseudogene in
the alpha-globin cluster. It was not detected by hybridization studies
but was found only on sequence analysis. Hardison et al. (1986)
suggested that 'divergent copies of a large number of genes may comprise
a substantial fraction of the slowly renaturing DNA of mammalian
genomes.' The newly detected pseudogene, which will be symbolized HBAP2,
is only 65 bp 3-prime to the polyadenylation site of zeta-1 (HBZP). The
sequence is: 5-prime--HBZ--HBZP--HBAP2--HBA2--HBA1--3-prime. (The
functional Hba gene of the mouse is on chromosome 11, but pseudogenes
are dispersed to other chromosomes (e.g., Hba-ps3 to mouse chromosome
15) (Popp et al., 1981; Leder et al., 1981; Eicher and Lee, 1991).)
Vandenplas et al. (1987) described a new form of alpha-0 thalassemia in
a South African family ascertained through a case of Hb H disease. A
novel deletion of 22.8-22.7 kb of DNA removed 3 pseudogenes as well as
the alpha-2 and alpha-1 genes. Since the alpha-2-globin gene encodes the
majority of alpha-globin, a thalassemic mutation of the alpha-1-globin
gene would be expected to result in a less severe loss of alpha-chain
synthesis. Moi et al. (1987) described an initiation codon mutation,
AUG-to-GUG, in the alpha-1-globin gene. As predicted, the degree of
interference with alpha-globin synthesis was less in this mutation than
in the mutation in the initiation codon of the alpha-2-globin gene (see
141850). Hill et al. (1987) described a unique nondeletion form of Hb H
disease in Papua New Guinea: all 4 alpha genes were intact. Hill et al.
(1987) commented on the striking difference in the hemoglobinopathies
that occur in Southeast Asia and in Melanesia. In the former area, Hb E,
Hb Constant Spring, and the Southeast Asian form of deletion
alpha-0-thalassemia are all common, whereas these forms have never been
found in Melanesians or Polynesians. Jarman and Higgs (1988) identified
a highly polymorphic region approximately 100 kb upstream of the
alpha-globin genes and referred to it as 5-prime HVR. This is a valuable
genetic marker for 16p. Higgs et al. (1989) gave a comprehensive review
of the molecular genetics of the alpha-globin gene cluster, including
its diseases.
Hatton et al. (1990) presented evidence for the existence of an
alpha-locus control region (LCRA; 152422). This would be comparable to
the beta-LCR which controls expression of the beta-like genes; see
152424. Liebhaber et al. (1990) identified an individual with
alpha-thalassemia in whom structurally normal alpha-globin genes were
inactivated in cis by a discrete de novo 35-kb deletion located about 30
kb 5-prime to the alpha-globin gene cluster. They concluded that the
deletion inactivates expression of the alpha-globin genes by removing
one or more of the previously identified upstream regulatory sequences
that are critical to expression of the alpha-globin genes.
Hemoglobinopathies of alpha-globin can result from missense mutations at
either of the 2 alpha-globin loci, HBA1 or HBA2. Since the normal HBA1
and HBA2 genes encode an identical alpha globin, these mutants cannot be
assigned to their specific loci on the basis of protein structural
analysis. A clue to the encoding locus, HBA1 versus HBA2, is provided by
the relative concentration of the alpha-globin mutant in the erythrocyte
based on the 2- to 3-fold higher level of expression of the HBA2 gene
(Liebhaber et al., 1986). However, since variables such as protein
stability, efficiency of hemoglobin tetramer formation, and other
factors can affect the steady-state levels of globin mutants, a
definitive locus assignment must be directly determined. Cash et al.
(1989) quantitated the expression of 2 alpha-globin structural mutants
found in the Caribbean basin, Fort de France and Spanish Town, and
showed that they are HBA1 and HBA2 mutants, respectively, on the basis
of low or high expression.
Wilkie et al. (1991) described major polymorphic length variation in the
terminal region of 16p (16p13.3) by physically linking the alpha-globin
locus with probes to telomere-associated repeats. They found 3 alleles
in which the alpha-globin genes lie 170 kb, 350 kb, or 430 kb from the
telomere. The 2 most common alleles were found to contain different
terminal segments, starting 145 kb distal to the alpha-globin genes.
Beyond this boundary these alleles are nonhomologous, yet each contains
sequences related to other, different chromosome termini. This
chromosome-size polymorphism probably arose by occasional exchanges
between the subtelomeric regions of nonhomologous chromosomes. Wilkie et
al. (1991) raised the possibility that the high frequency of trisomy 16
may be related to this nonhomology of the 2 common 16pter alleles in
their subtelomeric region.
Huisman et al. (1996) found that of the 141 codons of the alpha-globin
genes (there are no sequence differences between the coding regions of
the alpha-2 and alpha-1 genes), as many as 99 have been found to be
mutated; for several, 3 or 4 mutations have been discovered, while 5
mutations are known for codons 23, 75, and 94, and 6 for codon 141. The
mutations appear to occur at random; thus, either one of the 3 bases are
replaced in the 199 known alpha-globin gene mutants.
The suggestion that alpha(+)-thalassemia has achieved a high frequency
in some populations as a result of selection by malaria is based on a
number of epidemiologic studies. In the southwest Pacific region, there
is a striking geographic correlation between the frequency of
alpha(+)-thalassemia and the endemicity of Plasmodium falciparum. Allen
et al. (1997) undertook a prospective case-control study of children
with severe malaria on the north coast of Papua New Guinea, where
malaria transmission is intense and alpha(+)-thalassemia affects more
than 90% of the population (homozygotes comprise approximately 55% and
heterozygotes 37% of the population). Compared with normal children, the
risk of having severe malaria was 0.40 in alpha(+)-thalassemia
homozygotes and 0.66 in heterozygotes. Unexpectedly, the risk of
hospital admission with infections other than malaria also was reduced
to a similar degree in homozygotes (0.36) and heterozygotes (0.63). This
clinical study demonstrated that a malaria resistance gene protects
against disease caused by infections other than malaria. A reduction in
mortality greater than that attributable directly to malaria had been
observed after the prevention of malaria by insecticides,
chemoprophylaxis, and insecticide-impregnated bed nets. Previous
observations that direct malaria mortality cannot account for observed
hemoglobin S gene frequencies suggest that the findings of this study
may apply equally to other malaria resistance genes.
Fung et al. (1999) reported 3 cases of homozygous alpha-thalassemia who
survived beyond the newborn period, all with hypospadias. Review of the
literature identified 2 additional cases. Fung et al. (1999) suggested
that the hypospadias may have been secondary to the in utero edema
leading to failure of fusion of urogenital folds or due to defect or
deletion of another gene at 16p13.3.
For a review of hydrops fetalis caused by alpha-thalassemia, see Chui
and Waye (1998).
From work on the mouse model of alpha-thalassemia, Leder et al. (1999)
demonstrated that a normal beta-globin allele can act as a modifying
gene ameliorating the severity of alpha-thalassemia. They found that the
phenotype of alpha-thalassemia was strongly influenced by the genetic
background in which the mutation resided; when both mutant genes were on
a chromosome derived from strain 129, the phenotype was severe, whereas
it was mild when the gene was on a 129 chromosome and a C57BL/6
chromosome. Linkage mapping indicated that the modifying gene is very
tightly linked to the beta-globin locus (lod score = 13.3). Furthermore,
the severity of the phenotype correlated with the size of
beta-globin-containing inclusion bodies, which accumulate in red blood
cells and likely accelerate their destruction. The beta-major globin
chains encoded by the 2 strains differed by 3 amino acids, one of which
is a glycine-to-cysteine substitution at position 13. The cys13 should
be available for interchain disulfide bridging and consequent
aggregation between excess beta chains. This normal polymorphic
variation between murine beta-globin chains could account for the
modifying action of the unlinked beta-globin locus. Here, the variation
in severity of the phenotype would not depend on a change in the ratio
between alpha and beta chains but on the chemical nature of the normal
beta chain, which is in excess. This work also indicated that modifying
genes can be normal variants that, absent an apparent physiologic
rationale, may be difficult to identify on the basis of structure alone.
De Gobbi et al. (2006) identified a pathogenetic mechanism underlying a
variant form of the inherited blood disorder alpha-thalassemia.
Association studies of affected individuals from Melanesia localized the
disease trait to the telomeric region of human chromosome 16, which
includes the alpha-globin gene cluster, but no molecular defects were
detected by conventional approaches. After resequencing and using a
combination of chromatin immunoprecipitation and expression analysis on
a tiled oligonucleotide array, De Gobbi et al. (2006) identified a
gain-of-function regulatory single-nucleotide polymorphism (rSNP)
(141800.0218) in a nongenic region between the alpha-globin genes and
their upstream regulatory elements. The rSNP creates a new promoter-like
element that interferes with normal activation of all downstream
alpha-like globin genes. De Gobbi et al. (2006) concluded that their
work illustrates a strategy for distinguishing between neutral and
functionally important rSNPs, and it also identifies a pathogenetic
mechanism that could potentially underlie other genetic diseases.
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 that 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
isolation.
N.B.: Alpha-globin variants for which it is unknown whether HBA1 or HBA2
is involved have arbitrarily been included in this entry. Carver and
Kutlar (1995) listed 191 alpha-globin variants as of January 1995. The
syllabus by Huisman et al. (1996) listed 199 alpha-chain hemoglobin
variants as of January 1996. These included single-base mutations in the
alpha-2 and alpha-1 genes as well as 2-base mutations. Not included in
their syllabus were deletions in mutations that result in
alpha-thalassemia, even if such a change (point mutation or frameshift)
occurred in one of the coding regions of the gene. Information about the
alpha-thalassemias was provided by Higgs et al. (1989).
Allelic Variants:
.0001
HEMOGLOBIN AICHI
HBA1, HIS50ARG
See Harano et al. (1984) and Baudin et al. (1987).
.0002
HEMOGLOBIN ALBANY-GEORGIA
HEMOGLOBIN ALBANY-SUMA
HBA1, LYS11ASN
This was found in a clinically normal black female in Albany, Georgia
(Webber et al., 1983). See also Shimasaki et al. (1983).
.0003
HEMOGLOBIN ANANTHARAJ
HBA1, LYS11GLU
See Pootrakul et al. (1975).
.0004
HEMOGLOBIN ANN ARBOR
HBA1, LEU80ARG
See Adams et al. (1972) and Adams (1974).
.0005
HEMOGLOBIN ARYA
HBA1, ASP47ASN
See Rahbar et al. (1975).
.0006
HEMOGLOBIN ATAGO
HBA1, ASP85TYR
See Fujiwara (1970) and Fujiwara et al. (1971).
.0007
HEMOGLOBIN ATTLEBORO
HBA1, SER138PRO
See McDonald et al. (1990).
.0008
HEMOGLOBIN AZTEC
HBA1, MET76THR
See Shelton et al. (1985).
.0009
HEMOGLOBIN BARI
HBA1, HIS45GLN
See Marinucci et al. (1980).
.0010
HEMOGLOBIN BEIJING
HBA1, LYS16ASN
See Liang et al. (1982).
.0011
HEMOGLOBIN BIBBA
HBA1, LEU136PRO
See Kleihauer et al. (1968). (This is actually an allelic variant of the
HBA2 gene; see 141850.0030.)
.0012
HEMOGLOBIN BOURMEDES
HBA1, PRO37ARG
See Dahmane-Arbane et al. (1987).
.0014
HEMOGLOBIN BROUSSAIS
HEMOGLOBIN J (BROUSSAIS);;
HEMOGLOBIN TAGAWA I
HBA1, LYS90ASN
See de Traverse et al. (1966), Yanase et al. (1968), Vella et al.
(1970), and Fleming et al. (1978).
.0015
HEMOGLOBIN CATONSVILLE
HBA1, INS GLU, PRO37/GLU/THR38
See Virshup et al. (1988). Moo-Penn et al. (1989) identified insertion
of a glutamic acid residue between proline-37 and threonine-38 in an
unstable hemoglobin variant. The PCR-amplified fragment of the variant
gene showed insertion of a GAA codon. In the normal alpha-globin gene
cluster, GAG is the codon for glutamic acid. Moo-Penn et al. (1989)
suggested that this mutation may have resulted from nonhomologous
nonallelic gene conversion.
.0016
HEMOGLOBIN CHAD
HBA1, GLU23LYS
See Boyer et al. (1968).
.0017
HEMOGLOBIN CHAPEL HILL
HBA1, ASP74GLY
See Orringer et al. (1976).
.0018
HEMOGLOBIN CHESAPEAKE
HBA1, ARG92LEU
See Clegg et al. (1966) and Harano et al. (1983). Polycythemia is the
only clinical feature. This was the first polycythemia-producing variant
to be described (Charache et al., 1966).
.0019
HEMOGLOBIN CHIAPAS
HBA1, PRO114ARG
See Jones et al. (1968).
.0020
HEMOGLOBIN CHICAGO
HBA1, LEU136MET
See Bowman et al. (1986).
.0021
HEMOGLOBIN CHONGQING
HBA1, LEU2ARG
See Zeng et al. (1984).
.0022
HEMOGLOBIN CONTALDO
HBA1, HIS103ARG
Unstable hemoglobin due to disruption of hydrogen bond between alpha 103
(his) and beta 108 (asn) (Sciarratta et al., 1984).
.0023
HEMOGLOBIN CORDELE
HBA1, ASP47ALA
See Nakatsuji et al. (1984).
.0024
HEMOGLOBIN DAGESTAN
HBA1, LYS60GLU
See Spivak et al. (1981) and Lacombe et al. (1987).
.0025
HEMOGLOBIN DALLAS
HBA1, ASN97LYS
See Dysert et al. (1982).
.0026
HEMOGLOBIN DANESHGAH-TEHRAN
HBA1, HIS72ARG
See Rahbar et al. (1973) and de Weinstein et al. (1985).
.0027
HEMOGLOBIN DENMARK HILL
HBA1, PRO95ALA
See Wiltshire et al. (1972).
.0028
HEMOGLOBIN DUAN
HBA1, ASP75ALA
See Liang et al. (1981, 1988).
.0029
HEMOGLOBIN DUNN
HBA1, ASP6ASN
See Jue et al. (1979) and Baklouti et al. (1988).
.0030
HEMOGLOBIN ETOBICOKE
HBA1, SER84ARG
See Crookston et al. (1969) and Headlee et al. (1983).
.0031
HEMOGLOBIN EVANSTON
HBA1, TRP14ARG
Honig et al. (1982) first described Hb Evanston in 2 black families. See
also Moo-Penn et al. (1983).
Harteveld et al. (2004) found this rare variant alone and in the
presence of common alpha-thalassemia deletions in 3 independent Asian
cases.
.0032
HEMOGLOBIN FERNDOWN
HBA1, ASP6VAL
See Lee-Potter et al. (1981).
.0033
HEMOGLOBIN FONTAINEBLEAU
HBA1, ALA21PRO
Wajcman et al. (1989) found this substitution in an Italian family. The
substitution produced no change in the stability or oxygen binding
properties of the hemoglobin molecule. The electrophoretic properties
were, furthermore, identical to those of Hb A, with the exception of
isoelectric focusing in which the variant migrated like Hb A1c. Hb
J(Nyanza), another substitution at position alpha-21, likewise causes no
hematologic disorder.
.0034
HEMOGLOBIN FORT DE FRANCE
HBA1, HIS45ARG
See Braconnier et al. (1977). Cash et al. (1989) confirmed that this is
a mutant of the HBA1 gene.
.0035
HEMOGLOBIN G (AUDHALI)
HBA1, GLU23VAL
See Marengo-Rowe et al. (1968).
.0037
HEMOGLOBIN G (FORT WORTH)
HEMOGLOBIN FORT WORTH
HBA1, GLU27GLY
This variant was described in 2 black families. Unusually low (5%)
concentration was found in heterozygotes, perhaps because of decreased
ability of the abnormal alpha chain to form dimers with beta chains. See
Schneider et al. (1971) and Carstairs et al. (1985).
.0038
HEMOGLOBIN G (GEORGIA)
HBA1, PRO95LEU
See Huisman et al. (1970).
.0039
MOVED TO 141850.0054
.0040
HEMOGLOBIN G (NORFOLK)
HBA1, ASP85ASN
See Cohen-Solal et al. (1975) and Lorkin et al. (1975).
.0041
HEMOGLOBIN G (PEST)
HBA1, ASP74ASN
Hb G (Pest) and Hb J (Buda) (141850.0008), both alpha-chain mutants,
occurred together in a Hungarian male with erythrocytosis. The
occurrence of some normal Hb A in this man showed the existence of at
least 2 alpha loci. See Brimhall et al. (1970, 1974) and Hollan et al.
(1972). Using polymerase chain reaction (PCR) to amplify selectively
alpha-1 and alpha-2-globin cDNAs, Mamalaki et al. (1990) then hybridized
the cDNAs to synthetic oligonucleotides specific for either the normal
or the mutated sequence. Using this approach, the alpha-globin
structural mutants J-Buda and G-Pest were found to be encoded by the
alpha-2 and the alpha-1-globin genes, respectively. The substitution in
G-Pest was a change from GAC to AAC at codon 74.
.0042
HEMOGLOBIN G (TAICHUNG)
HEMOGLOBIN Q;;
HEMOGLOBIN Q (THAILAND);;
HEMOGLOBIN MAHIDOL;;
HEMOGLOBIN ASABARA;;
HEMOGLOBIN KURASHIKI
HBA1, ASP74HIS
See Vella et al. (1958), Gammack et al. (1961), Lie-Injo et al. (1966,
1979); Blackwell and Liu (1970), Pootrakul and Dixon (1970), Lorkin et
al. (1970), Iuchi et al. (1978), and Higgs et al. (1980). Zeng et al.
(1992) demonstrated that the mutation is due to a GAC-to-CAC change in
codon 74 of the HBA1 gene. They developed a simple and accurate method
for diagnosis of the Hb Q (Thailand) variant based on restriction enzyme
analysis.
.0043
HEMOGLOBIN G (WAIMANALO)
HEMOGLOBIN AIDA
HBA1, ASP64ASN
See Blackwell et al. (1973) and Bunn et al. (1978). Schiliro et al.
(1991) found this variant in a Filipino mother and child living in
Sicily. They showed no hematologic abnormalities.
.0044
HEMOGLOBIN GARDEN STATE
HBA1, ALA82ASP
See Winter et al. (1978).
.0045
HEMOGLOBIN GRADY
HEMOGLOBIN DAKAR
HBA1, 3AA INS, 118THR-GLU-PHE119
At the time it was first studied by Huisman et al. (1974), hemoglobin
Grady was unique in having an insertion of threonine-glutamic
acid-phenylalanine between amino acids 118 and 119 of the alpha chain.
Several hemoglobins with deletions were then known (Leiden, Lyon,
Freiburg, Niteroi, Tochigi, St. Antoine, Tours and Gun Hill). Scott et
al. (1981) found no evidence of an extra (fifth) alpha gene. They
argued, therefore, that if, as supposed, Hb Grady arose by unequal
crossing over, the event occurred between alleles rather than between
the separate alpha-1 and alpha-2 loci. The glu-phe-thr insertion is a
repeat of normal residues 116, 117 and 118. See Cleek et al. (1983).
Substitution of glutamine for histidine at alpha 112 was thought to be
the change in hemoglobin Dakar; however, on restudy the hemoglobin was
found to be identical to Hb Grady (Garel et al., 1976).
.0046
HEMOGLOBIN GUANGZHOU
HEMOGLOBIN HANGZHOU
HBA1, ASP64GLY
See Jen and Liu (1987), Zhou et al. (1987), and Li et al. (1990).
.0047
HEMOGLOBIN GUIZHOU
HEMOGLOBIN UTSUNOMIYA
HBA1, PRO77ARG
See Hattori et al. (1985).
.0048
HEMOGLOBIN HANDA
HEMOGLOBIN MUNAKATA
HBA1, LYS90MET
See Harano et al. (1982) and Sugihara et al. (1983).
.0049
HEMOGLOBIN HANDSWORTH
HBA1, GLY18ARG
See Griffiths et al. (1977), Chih-chuan et al. (1981), and Al-Awamy et
al. (1985).
.0050
HEMOGLOBIN HARBIN
HBA1, LYS16MET
See Zeng et al. (1984).
.0051
HEMOGLOBIN HEKINAN
HBA1, GLU27ASP
See Harano et al. (1988). Using dot-blot analysis of amplified DNA with
(32)p-labeled probes, Zhao et al. (1990) located the mutation in codon
27 of the minor alpha-1 globin gene and showed that the change involved
a GAG (glutamic acid)-to-GAT (aspartic acid) mutation. Their patients
were 3 Chinese women from Macau.
In Thailand, Ngiwsara et al. (2004) described 2 unrelated cases of
compound heterozygosity for Hb Hekinan and alpha-thalassemia.
.0052
HEMOGLOBIN HIROSAKI
HBA1, PHE43LEU
See Ohba et al. (1975, 1978).
.0053
HEMOGLOBIN HOBART
HBA1, HIS20ARG
See Fleming et al. (1987).
.0054
HEMOGLOBIN HOPKINS 2
HBA1, HIS112ASP
Fast hemoglobin. See Smith and Torbert (1958), Itano and Robinson
(1960), Bradley et al. (1961), Ostertag et al. (1972), Clegg and
Charache (1978).
.0055
HEMOGLOBIN I
HEMOGLOBIN I (BURLINGTON);;
HEMOGLOBIN I (PHILADELPHIA);;
HEMOGLOBIN I (SKAMANIA);;
HEMOGLOBIN I (TEXAS)
HBA1, LYS16GLU
Fast hemoglobin. Substitution of aspartic acid for lysine at alpha 16
was first reported by Murayama (1962). However, Crick pointed out that
this substitution could not be accomplished by change in one base.
Restudy by Beale and Lehmann (1965) and by Schneider et al. (1966)
showed substitution of glutamic acid for lysine. Hemoglobin I was
thought to show sickling but this has been shown to be due to faulty
technique (Schneider et al., 1967). See Rucknagel et al. (1955),
Schwartz et al. (1957), Itano and Robinson (1959, 1960), Ranney et al.
(1962), O'Brien et al. (1964), Thompson et al. (1965), Schneider et al.
(1966), Bowman and Barnett (1967), Baur (1968), Labossiere and Vella
(1971), Fleming et al. (1978), and Liebhaber et al. (1984). The
hemoglobin I mutation is curious in that the mutation is present in HBA2
(141850.0011) as well as in HBA1.
.0057
HEMOGLOBIN IWATA
HBA1, HIS87ARG
See Shibata et al. (1980) and Liu et al. (1983).
.0058
HEMOGLOBIN J (ABIDJAN)
HBA1, GLY51ASP
See Cabannes et al. (1972).
.0059
HEMOGLOBIN J (ANATOLIA)
HBA1, LYS61THR
See Giordano et al. (1990).
.0060
HEMOGLOBIN J (BIRMINGHAM)
HEMOGLOBIN J (MEERUT)
HBA1, ALA120GLU
See Kamuzora and Lehmann (1974) and Blackwell et al. (1974).
.0062
HEMOGLOBIN J (CAMAGUEY)
HBA1, ARG141GLY
See Martinez et al. (1978). Romero et al. (1995) found this hemoglobin
variant in 3 Spanish families. The original description by Martinez et
al. (1978) was in a Cuban family of Spanish ancestry.
.0063
HEMOGLOBIN J (CAPE TOWN)
HBA1, ARG92GLN
See Botha et al. (1966), Harano et al. (1983), and Lambridis et al.
(1986).
.0064
HEMOGLOBIN J (CUBUJUQUI)
HBA1, ARG141SER
See Saenz et al. (1977) and Moo-Penn et al. (1981).
.0065
HEMOGLOBIN J (HABANA)
HBA1, ALA71GLU
See Colombo et al. (1974) and Ohba et al. (1983).
.0066
HEMOGLOBIN J (KUROSH)
HBA1, ALA19ASP
See Rahbar et al. (1976).
.0067
HEMOGLOBIN J (MEDELLIN)
HBA1, GLY22ASP
See Gottlieb et al. (1964).
.0068
HEMOGLOBIN J (NYANZA)
HBA1, ALA21ASP
See Kendall et al. (1973).
.0070
HEMOGLOBIN J (PARIS 1)
HEMOGLOBIN J (ALJEZUR)
HBA1, ALA12ASP
See Rosa et al. (1966), Trincao et al. (1968), and Marinucci et al.
(1979).
.0071
HEMOGLOBIN J (RAJAPPEN)
HBA1, LYS90THR
See Hyde et al. (1971).
.0072
HEMOGLOBIN J (ROVIGO)
HBA1, ALA53ASP
See Alberti et al. (1974) and Moo-Penn et al. (1978).
.0074
HEMOGLOBIN J (SINGA)
HBA1, ASN78ASP
See Wong et al. (1984).
.0075
HEMOGLOBIN J (SINGAPORE)
HBA1, ASN78ASP AND ALA79GLY
Since no simple frameshift mechanism could be imagined, the possibility
of 2 separate mutations was favored by Blackwell et al. (1972), who
suggested that 2 separate hemoglobins, appropriately called Hb J (Singa)
and Hb J (Pore), will be discovered eventually. Double mutation on the
same chromosome would seem more likely than crossing-over in a compound
heterozygote since the 2 codons involved are contiguous.
.0076
HEMOGLOBIN J (TASHIKUERGAN)
HBA1, ALA19GLU
See Houjun et al. (1984). Li et al. (1990) found this variant in
populations in the Silk Road region of China.
.0077
HEMOGLOBIN J (TONGARIKI)
HBA1, ALA115ASP
See Gajdusek et al. (1967) and Beaven et al. (1972). A homozygous
individual had only anomalous hemoglobin suggesting the existence of
only one alpha locus in Melanesians (Abramson et al., 1970).
.0078
HEMOGLOBIN J (TORONTO)
HBA1, ALA5ASP
See Crookston et al. (1965).
.0079
HEMOGLOBIN JACKSON
HBA1, LYS127ASN
See Moo-Penn et al. (1976).
.0080
HEMOGLOBIN KARACHI
HBA1, ALA5PRO
See Ahmad et al. (1986).
.0081
HEMOGLOBIN KARIYA
HBA1, LYS40GLU
See Harano et al. (1983) and Imai et al. (1989).
.0082
HEMOGLOBIN KAWACHI
HBA1, PRO44ARG
See Harano et al. (1982).
.0083
HEMOGLOBIN KOELLIKER
HEMOGLOBIN F (KOELLIKER)
HBA1, ARG141DEL
Not a genetic change. The C-terminal amino acid, 141, of the alpha chain
(arginine) is missing, probably from the action of a carboxypeptidase
present in normal plasma. This unusual fast hemoglobin is observed in
persons with hemolysis. The change can occur in fetal hemoglobin also
(Kohne et al., 1977). See Marti et al. (1967) and Schiliro et al.
(1982).
.0084
HEMOGLOBIN KOKURA
HEMOGLOBIN BEILINSON;;
HEMOGLOBIN MICHIGAN-I;;
HEMOGLOBIN MICHIGAN-II;;
HEMOGLOBIN L (GASLINI);;
HEMOGLOBIN TAGAWA II;;
HEMOGLOBIN UMI;;
HEMOGLOBIN MUGINO;;
HEMOGLOBIN YUKUHASHI-2
HBA1, ASP47GLY
See Yamaoka et al. (1960), Ooya et al. (1961), Sumida (1975), and Ohba
et al. (1982). The change is in TP IV (DeVries et al., 1963).
.0086
HEMOGLOBIN L (PERSIAN GULF)
HBA1, GLY57ARG
See Rahbar et al. (1969).
.0087
HEMOGLOBIN LEGNANO
HBA1, ARG141LEU
See Mavilio et al. (1978).
.0088
HEMOGLOBIN LE LAMENTIN
HBA1, HIS20GLN
See Sellaye et al. (1982), Harano et al. (1983), and Malcorra-Azpiazu et
al. (1988).
.0089
HEMOGLOBIN LILLE
HBA1, ASP74ALA
See Djoumessi et al. (1981) and Lu et al. (1984).
.0090
HEMOGLOBIN LOIRE
HBA1, ALA88SER
This variant was discovered in a 10-year-old Algerian boy born in Loire.
The child had erythrocytosis and microcytosis, the latter being due to
iron deficiency (Baklouti et al., 1988).
.0091
HEMOGLOBIN LUXEMBOURG
HBA1, TYR24HIS
Groff et al. (1989) found this substitution in association with mild
hemolytic anemia and increased indirect bilirubinemia in a family
originating from the Netherlands.
.0092
HEMOGLOBIN M (BOSTON)
HEMOGLOBIN GOTHENBURG;;
HEMOGLOBIN M (GOTHENBURG);;
HEMOGLOBIN M (OSAKA);;
HEMOGLOBIN M (KISKUNHALAS)
HBA1, HIS58TYR
The aberrant hemoglobins associated with methemoglobinemia are referred
to as hemoglobin M. Most of the hemoglobin M variants have substitutions
of histidine at alpha 58, alpha 87, beta 63, or beta 92. These 4 amino
acids are critical to the binding of the heme group. The exception is
hemoglobin M (Milwaukee-1). See Gerald et al. (1957), Hansen et al.
(1960), Gerald and Efron (1961), Betke (1962), Hayashi et al. (1964),
Shimizu et al. (1965), Suzuki et al. (1965), Hollan et al. (1967), and
Pulsinelli et al. (1973).
.0093
HEMOGLOBIN M (IWATE)
HEMOGLOBIN M (KANKAKEE);;
HEMOGLOBIN M (OLDENBURG);;
HEMOGLOBIN M (SENDAI)
HBA1, HIS87TYR
Hb Iwate was the first variant hemoglobin found in Japan (Shibata et
al., 1960). Familial cyanosis had been recognized for about 200 years in
the prefecture of Iwate in Honshu, where about 70 affected persons were
identified in the 1950s. It was called 'kuchikuro,' or 'blackmouth.' In
each form of methemoglobinemia, the heme iron is stabilized in the
ferric form. Patients with the Hb M alpha forms are cyanotic at birth;
those with the Hb M beta forms are usually not cyanotic until they are 3
months of age. Horst et al. (1987) showed that the Iwate mutation
involves the alpha-1 globin gene. Specifically, they demonstrated a
CAC-to-TAC mutation in codon 87 of that gene. They showed that the Iwate
mutation can be identified directly on RsaI digestion. See Meyering et
al. (1960), Shibata et al. (1961), Gerald and Efron (1961), Miyaji et
al. (1962), Heller (1962), Heller et al. (1962), Tonz et al. (1962),
Shibata (1964), Tamura (1964), Shimizu et al. (1965), Pik and Tonz
(1966), Maggio et al. (1981), and Mayne et al. (1986).
Ameri et al. (1999) likewise determined that the molecular defect in 2
patients with Hb M (Kankakee) was his87 to tyr in the HBA1 gene. The
proportion of Hb M (Kankakee) observed was higher than that predicted
for an alpha-1-globin variant. They presented evidence suggesting that
the greater-than-expected proportion of Hb M (Kankakee) results from
preferential association of the electronegative beta-globin chains with
the alpha-(M)-globin chains that are more electropositive than normal
alpha-globin chains.
.0094
MOVED TO 141850.0047
.0095
HEMOGLOBIN MATSUE-OKI
HBA1, ASP75ASN
See Ohba et al. (1977) and Yi-Tao et al. (1982).
.0096
HEMOGLOBIN MEMPHIS
HBA1, GLU23GLN
Substitution of glutamine for glutamic acid at alpha 23. A hemoglobin S
homozygote who also carries this abnormal hemoglobin has a mild form of
sickle cell anemia. See Kraus et al. (1965, 1967) and Cooper et al.
(1973).
.0097
HEMOGLOBIN MEXICO
HEMOGLOBIN J;;
HEMOGLOBIN J (MEXICO);;
HEMOGLOBIN J (PARIS 2);;
HEMOGLOBIN UPPSALA
HBA1, GLN54GLU
Fast hemoglobin. See Jones et al. (1963, 1968), Beckman et al. (1966),
Labie and Rosa (1966), Quattrin and Ventruto (1967), Fessas et al.
(1969), and Trabuchet et al. (1982).
.0098
HEMOGLOBIN MILLEDGEVILLE
HBA1, PRO44LEU
See Honig et al. (1980).
.0099
HEMOGLOBIN MIYANO
HBA1, THR41SER
See Ohba et al. (1989).
.0100
HEMOGLOBIN MIZUSHI
HBA1, ASP75GLY
No hematologic abnormality. See Iuchi et al. (1980).
.0101
HEMOGLOBIN MOABIT
HBA1, LEU86ARG
See Knuth et al. (1979).
.0104
HEMOGLOBIN NECKER ENFANTS-MALADES
HBA1, HIS20TYR
This variant was detected by chromatography in the course of screening
diabetics for Hb A1c (Wajcman et al., 1980).
.0105
HEMOGLOBIN NIGERIA
HBA1, SER81CYS
See Honig et al. (1978).
.0106
HEMOGLOBIN NOKO
HBA1, MET76LYS
See Shibata et al. (1981).
.0107
HEMOGLOBIN NORFOLK
HEMOGLOBIN J (NORFOLK);;
HEMOGLOBIN KAGOSHIMA;;
HEMOGLOBIN NISHIK
HBA1, GLY57ASP
Fast hemoglobin. See Ager et al. (1958), Baglioni (1962), Huntsman et
al. (1963), Hanada et al. (1964), Imamura (1966), and Lehmann and
Carrell (1969).
.0108
HEMOGLOBIN NOUAKCHOTT
HBA1, PRO114LEU
See Wajcman et al. (1989).
.0109
HEMOGLOBIN NUNOBIKI
HBA1, ARG141CYS
This hemoglobin showed an extremely high oxygen affinity. The patient,
who had 'marginal erythrocytosis,' was shown to have 13.1% Hb Nunobiki
(Shimasaki, 1985).
.0110
HEMOGLOBIN O (INDONESIA)
HEMOGLOBIN O (BUGINESE-X);;
HEMOGLOBIN BUGINESE-X;;
HEMOGLOBIN O (OLIVIERE);;
HEMOGLOBIN OLIVIERE
HBA1, GLU116LYS
See Lie-Injo and Sadono (1958), Baglioni and Lehmann (1962), and Sansone
et al. (1970).
Daud et al. (2001) investigated the occurrence of hemoglobin O
(Indonesia) in related ethnic populations of the Indonesian archipelago.
Nineteen individuals heterozygous for this variant were identified in 4
ethnic populations. The level of Hb O (Indonesia) in 17 of the
individuals was 11.6 +/- 1.0%, significantly lower than the expected 17
to 22%, indicating the instability of Hb O (Indonesia).
.0111
HEMOGLOBIN O (PADOVA)
HBA1, GLU30LYS
See Vettore et al. (1974), Kilinc et al. (1985), and Martin et al.
(1990). Schnedl et al. (1997) showed that the silent hemoglobin O Padova
mutation causes an additional peak on high performance liquid
chromatography (HPLC) and falsely low HbA(1c) values (glycated
hemoglobin) when measured by HPLC. HPLC is the gold standard for
evaluation of glycated hemoglobin in diabetes mellitus.
.0112
HEMOGLOBIN OGI
HEMOGLOBIN QUEENS
HBA1, LEU34ARG
See Sugihara et al. (1982), Moo-Penn et al. (1982), and Yongsuwan et al.
(1987). This has been shown to be a mutation of the HBA1 gene (Cash et
al., 1989).
.0113
HEMOGLOBIN OLEANDER
HBA1, GLU116GLN
See Schneider et al. (1980).
.0114
HEMOGLOBIN OTTAWA
HEMOGLOBIN SIAM
HBA1, GLY15ARG
See Vella et al. (1974) and Pootrakul et al. (1974).
Yodsowan et al. (2000) studied this variant in a 21-year-old Thai female
and her mother. Turbpaiboon et al. (2002) reported a fourth case of Hb
Siam in a healthy Thai female and concluded that there is no
alpha-thalassemic effect of the variant.
.0115
HEMOGLOBIN OWARI
HBA1, VAL121MET
This is a neutral-to-neutral change; it was detected in the course of
mass screening by isoelectric focusing (Harano et al., 1986).
.0116
HEMOGLOBIN PERSPOLIS
HBA1, ASP64TYR
See Rahbar et al. (1976).
.0117
HEMOGLOBIN PETAH TIKVA
HBA1, ALA110ASP
See Honig et al. (1981).
.0118
HEMOGLOBIN PONTOISE
HEMOGLOBIN J (PONTOISE)
HBA1, ALA63ASP
See Thillet et al. (1977) and Gonzalez-Redondo et al. (1987).
.0119
HEMOGLOBIN PORT PHILLIP
HBA1, LEU91PRO
See Brennan et al. (1977).
.0120
MOVED TO 141850.0055
.0121
HEMOGLOBIN Q (INDIA)
HBA1, ASP64HIS
See Sukumaran et al. (1972) and Schmidt et al. (1976).
.0122
HEMOGLOBIN Q (IRAN)
HBA1, ASP75HIS
See Lorkin et al. (1970), Lie-Injo et al. (1979), and Higgs et al.
(1980).
.0123
MOVED TO 141850.0052
.0124
HEMOGLOBIN REIMS
HBA1, GLU23GLY
See Bardakdjian-Michau et al. (1989).
.0125
HEMOGLOBIN RUSS
HBA1, GLY51ARG
See Huisman and Sydenstricker (1962) and Reynolds and Huisman (1966).
This has been shown to be a mutation of the HBA1 gene (Cash et al.,
1989).
.0126
HEMOGLOBIN SASSARI
HBA1, ASP126HIS
Masala et al. (1987) first described this variant as an
electrophoretically slow-moving hemoglobin in 2 brothers affected by
erythrocytosis with slight microcytosis. In a large screening program
involving 20,000 people in the city of Sassari and its surrounding area
in Sardinia, Masala (1992) found the variant in 3 other apparently
unrelated subjects. A male of German origin was identified by
Bardakdjian-Michau et al. (1990) as a carrier of the same mutation.
Sanna et al. (1994) demonstrated that the adult variant has increased
oxygen affinity, a dramatic reduction of homotropic interactions, and a
significant decrease of the effect of 2,3-diphosphoglycerate (35% lower
than that observed for Hb A). The fetal variant also showed increased
oxygen affinity compared with normal Hb F and an almost abolished
heme-heme interaction.
Paglietti et al. (1998) demonstrated that Hb Sassari results from a GAC
(asp)-to-CAC (his) mutation in the HBA1 gene.
.0127
HEMOGLOBIN SAVARIA
HBA1, SER49ARG
See Szelenyi et al. (1980), Juricic et al. (1985), Ojwang et al. (1985),
and Suarez et al. (1985).
.0128
HEMOGLOBIN SAWARA
HBA1, ASP6ALA
No pathologic effects were observed (Sumida et al., 1973; Sumida, 1975).
.0130
HEMOGLOBIN SETIF
HBA1, ASP94TYR
See Wajcman et al. (1972), Nozari et al. (1977), Al-Awamy et al. (1985),
and Abdo (1989). Schiliro et al. (1991) found this hemoglobin variant in
Sicily.
Dincol et al. (2003) stated that Hb Setif was first described in an
Algerian family (Wajcman et al., 1972) and subsequently in Iranian,
African, Saudi Arabian, and Maltese populations. They identified the
variant in a Turkish family. Heterozygotes were asymptomatic.
.0131
HEMOGLOBIN SHAARE ZEDEK
HBA1, LYS56GLU
See Abramov et al. (1980).
.0132
HEMOGLOBIN SHENYANG
HBA1, ALA26GLU
See Zeng et al. (1982) and Yi et al. (1989).
.0133
HEMOGLOBIN SHIMONOSEKI
HEMOGLOBIN HIKOSHIMA
HBA1, GLN54ARG
See Yamaoka et al. (1960) and Hanada and Rucknagel (1964).
.0134
HEMOGLOBIN SHUANGFENG
HBA1, GLU27LYS
See Liang et al. (1981).
.0135
HEMOGLOBIN SINGAPORE
HBA1, ARG141PRO
See Clegg et al. (1969).
.0137
HEMOGLOBIN ST. CLAUDE
HBA1, LYS127THR
See Vella et al. (1974).
.0138
HEMOGLOBIN ST. LUKE'S
HBA1, PRO95ARG
See Bannister et al. (1972).
Felice (2003) cited evidence that Hb St. Luke's is a mutation of the
HBA1 gene.
.0139
HEMOGLOBIN STANLEYVILLE-II
HBA1, ASN78LYS
See Van Ros et al. (1968), North et al. (1980), and Rhoda et al. (1983).
Costa et al. (1991) described a family with 1 homozygote and 3
heterozygotes for Hb Stanleyville II. The pattern of restriction
fragments demonstrated an associated 3.7-kb alpha-globin gene deletion.
.0140
HEMOGLOBIN STRUMICA
HEMOGLOBIN SERBIA
HBA1, HIS112ARG
See Niazi et al. (1975) and Beksedic et al. (1975).
.0143
HEMOGLOBIN SUNSHINE SETH
HBA1, ASP94HIS
See Schroeder et al. (1979).
.0144
HEMOGLOBIN SURESNES
HBA1, ARG141HIS
See Poyart et al. (1976) and Saenz et al. (1978).
.0145
HEMOGLOBIN SWAN RIVER
HBA1, ASP6GLY
See Moo-Penn et al. (1987). Harano et al. (1996) observed this variant
in a Japanese man with mild polycythemia.
.0147
HEMOGLOBIN THAILAND
HBA1, LYS56THR
See Pootrakul et al. (1977).
.0148
HEMOGLOBIN TITUSVILLE
HBA1, ASP94ASN
See Schneider et al. (1975).
.0149
HEMOGLOBIN TOKONAME
HBA1, LYS139THR
See Harano et al. (1983).
.0150
HEMOGLOBIN TORINO
HBA1, PHE43VAL
See Beretta et al. (1968) and Prato et al. (1970).
.0151
HEMOGLOBIN TOTTORI
HBA1, GLY59VAL
See Nakatsuji et al. (1981).
.0152
HEMOGLOBIN TOYAMA
HEINZ BODY HEMOLYTIC ANEMIA
HBA1, LEU136ARG
This hemoglobin variant is associated with congenital Heinz body anemia
(Ohba et al., 1987).
.0153
HEMOGLOBIN TWIN PEAKS
HBA1, LEU113HIS
See Guis et al. (1985). This has been shown to be a mutation of the HBA1
gene (Cash et al., 1989).
.0154
HEMOGLOBIN UBE-2
HBA1, ASN68ASP
See Miyaji et al. (1967). In Turkey, Bilginer et al. (1984) found the
first instance of Hb Ube-2 outside Japan. It occurred in other members
of the family.
Cotton et al. (2000) found this rare variant during universal neonatal
screening. The patients had normal hematologic parameters. The variant
was found in twins and an older sister and in the father; both parents
were of Belgian ancestry.
Shin et al. (2002) described the disorder in a Taiwanese subject.
.0155
HEMOGLOBIN UBE-4
HBA1, GLU116ALA
See Ohba et al. (1978).
.0156
HEMOGLOBIN WESTMEAD
HBA1, HIS122GLN
This variant was found in a Chinese woman (Fleming et al., 1980). See
Liang et al. (1988).
.0157
HEMOGLOBIN WINNIPEG
HBA1, ASP75TYR
See Vella et al. (1973) and Nakatsuji et al. (1983). This has been shown
to be a mutation of the HBA1 gene (Cash et al., 1989).
.0158
HEMOGLOBIN WOODVILLE
HBA1, ASP6TYR
Since alpha-6 asp is involved in salt linkage with alpha-127 lys of the
same chain, the increased oxygen affinity of hemoglobin variants at this
position probably reflects loss of this salt bridge in the deoxy state.
Similar changes have been observed for Hb St. Claude which also cannot
form the salt bridge because of substitution of threonine for lysine at
alpha-127. See Como et al. (1986).
.0159
HEMOGLOBIN WUMING
HEMOGLOBIN J (WENCHANG-WUMING)
HBA1, LYS11GLN
See Zeng et al. (1981). Qualtieri et al. (1995) found this
fast-migrating hemoglobin variant in a pregnant woman living in Italy.
.0160
HEMOGLOBIN ZAMBIA
HBA1, LYS60ASN
See Barclay et al. (1969).
.0161
HEMOGLOBIN BELLIARD
HBA1, LYS56ASN
See Wajcman et al. (1990).
.0162
HEMOGLOBIN TONOSHO
HBA1, ALA110THR
In the course of measuring hemoglobin A1c by automated cation exchange
high performance liquid chromatography, Ohba et al. (1990) detected a
new alpha-chain variant: substitution of alanine by threonine at
position 110. The abnormal alpha chain comprised about 14% of the total
alpha chain.
.0163
HEMOGLOBIN FUKUTOMI
HBA1, ASP126VAL
This hemoglobin, which has a high affinity for oxygen, was detected in a
Japanese male during a screening survey. The proband was a 53-year-old
man with liver cirrhosis and hemorrhagic gastritis (Hidaka et al.,
1990).
.0164
HEMOGLOBIN PORT HURON
HBA1, LYS56ARG
Zwerdling et al. (1991) investigated the structural abnormality of a
putative Hb E detected in an African American family with no apparent
Asian ancestry. The tryptic peptide map formed by high performance
liquid chromatography showed that the electrophoretic variant was indeed
the beta glu26-to-lys mutation of Hb E. In addition, however, the
tryptic map showed an abnormal alpha peptide. The second mutation was a
substitution of arginine for lysine at residue 56 of the alpha chain.
The variant was clinically silent.
.0166
HEMOGLOBIN PAVIE
HBA1, VAL135GLU
See Wajcman et al. (1990).
.0167
HEMOGLOBIN QUESTEMBERT
HBA1, SER131PRO
See Wajcman et al. (1990, 1993).
.0168
HEMOGLOBIN THIONVILLE
HBA1, NH2 EXTENSION, VAL1GLU
See Vasseur et al. (1990). Substitution of glutamic acid for valine as
the first residue in the mature protein is accompanied by retention of
the initiator methionine residue. This may be the only known hemoglobin
variant with an NH2-extension in the alpha-globin chain. Hb Marseille
(141900.0171), Hb Doha (141900.0069), and Hb South Florida (141900.0266)
are examples of hemoglobin variants with an NH2-extension due to
retention of the initiator methionine in the beta-globin chain. Each is
due to mutation in the first or second residue of the mature protein.
Vasseur et al. (1992) found that elongation of the NH2-terminus of the
alpha-chain, due to inhibition of cleavage of the initiator methionine
which is then acetylated, modifies the 3-dimensional structure of
hemoglobin at a region that is known to have an important role in the
allosteric regulation of oxygen binding. Hb Thionville has a lowered
affinity for oxygen. In contrast, response to 2,3-diphosphoglycerate is
normal.
.0169
HEMOGLOBIN KANAGAWA
HBA1, LYS40MET
In the course of a high performance liquid chromatography survey of Hb
A1c, Miyashita et al. (1992) detected a new hemoglobin in a 70-year-old
Japanese male with cerebral infarction and erythremia. Further studies
revealed a lys40-to-met mutation. The variant showed increased oxygen
affinity, decreased heme-heme interaction, and a lowered
2,3-diphosphoglycerate effect.
(Erythemia, a now almost obsolete synonym for polycythemia and
erythrocytosis, means increased red blood cell mass.)
.0170
HEMOGLOBIN TURRIFF
HBA1, LYS99GLU
In a diabetic woman of Scottish ancestry, Langdown et al. (1992)
detected a new hemoglobin variant in the course of determining Hb A1c by
high performance liquid chromatography. The abnormal hemoglobin
chromatographed with the Hb A1c fraction. Family studies showed that a
lys99-to-glu mutation, which was not associated with any hematologic
disturbance, had occurred de novo. An AAG-to-GAG mutation was presumed
and was not assigned to either the alpha-2- or alpha-1-globin chain.
The Hb A(1c) level in the patient of Langdown et al. (1992) was found to
be very high. In a Japanese individual, Harano et al. (2003) likewise
found an unexpectedly high Hb A(1c) level as measured by an automatic Hb
A(1c) analyzer and found by DNA sequencing a change in the first
nucleotide of codon 99 (AAG-GAG) of the Hb A1 gene.
.0171
HEMOGLOBIN ZAIRE
HBA1, 15-BP TANDEM REPEAT
Hemoglobin Zaire was found in a 36-year-old patient from Zaire during a
systematic hemoglobin study. Wajcman et al. (1992) demonstrated that the
abnormality was the insertion of 5 amino acids--his, leu, pro, ala,
glu--between glu116 and phe117 of the alpha-globin chain. This sequence
represented a tandem repeat of the 5 amino acid residues from 112
through 116, located at the end of the GH corner of the molecule.
Hemoglobin Grady (141800.0045) involves the insertion of 3 amino acids
as repeats of residues 116, 117 and 118. Unequal crossing over between
alleles rather than between the separate alpha-1 and alpha-2 loci was
thought to be the mechanism in that case and possibly in the case of Hb
Zaire as well.
.0172
HEMOGLOBIN LUTON
HBA1, HIS89LEU
In a newborn infant and the father, a 35-year-old Pakistani man,
Williamson et al. (1992) described a new hemoglobin with high oxygen
affinity. The high affinity hemoglobin mutation was identified by HPLC
peptide mapping and amino acid sequencing; leucine was substituted for
histidine at amino acid position 89. The mutation occurred at the end of
the F helix (FG1), a part of the hemoglobin structure critical in
determining oxygen affinity since it is directly linked to the heme iron
through the proximal histidine residue F8. This was the first example of
a mutation at this position of the alpha chain of hemoglobin, although
there were 2 high affinity mutants that involved the structurally
equivalent amino acid (beta94 asp) of the beta chain: Hb Barcelona
(beta94 his; 141900.0016) and Hb Bunbury (beta94 asn; 141900.0035). The
new hemoglobin was called Hb Luton for the name of the hospital where
the proband was originally treated. The proband was a neonate in whom 2
abnormal hemoglobin bands were found, the 2 bands being the mutant forms
of fetal and adult hemoglobins containing the anomalous alpha globin.
The father had microcytosis as well as mild polycythemia and was shown
to have an accompanying alpha-thalassemia trait due to deletion of a
single alpha-globin gene.
.0173
HEMOGLOBIN OZIERI
HBA1, ALA71VAL
During a screening for hemoglobinopathies in Sardinia, Ferranti et al.
(1993) found a new 'silent' hemoglobin variant in 5 apparently unrelated
newborn babies. The variant was detected by means of isoelectric
focusing (IEF), and further study revealed a valine for alanine
substitution at position 71 of the alpha-globin chain. The substitution
indicated that a C-to-T transition had occurred in the GCG codon for
alanine which contains one of the 35 unmethylated CpG dinucleotides of
the HBA1 gene. This observation brought to 13 the number of variants due
to mutation in the CpGs of the HBA1 gene and raised the possibility that
unmethylated CpGs, like methylated ones, may be hotspots for mutations.
.0174
HEMOGLOBIN ADANA
HBA1, GLY59ASP
In 3 Turkish children with severe thalassemia, Curuk et al. (1992) found
a GGC-to-GAC mutation in codon 59 of the HBA1 gene resulting in a
replacement of glycine by aspartic acid. The combination of an
alpha-thal-1 deletion with the unstable Hb Adana resulted in a severe
type of Hb H disease.
.0175
HEMOGLOBIN AL-AIN ABU DHABI
HBA1, GLY18ASP
During a routine program of hemoglobin screening performed in the United
Arab Emirates, Abbes et al. (1992) found an electrophoretically
fast-moving variant in a 9-month-old girl and in several members of her
family. Amino acid sequencing demonstrated that the new variant had a
gly18-to-asp substitution. Its functional properties were normal.
.0176
HEMOGLOBIN POITIERS
HBA1, HIS45ASP
Hb Poitiers was discovered by Bardakdjian et al. (1994) in a 9-year-old
French Caucasian boy who suffered from chronic anemia. The molecular
defect consists of a missense mutation at codon 45 of the HBA1 gene,
changing histidine to aspartate. Hb Poitiers displays a 2-fold increased
oxygen affinity, a slightly decreased heme-heme interaction, and a
slightly faster autooxidation rate. In adult hemoglobin (Hb A), the
histidine residue at position 45 of the alpha-globin gene is the only
polar contact between the heme group and globin. This position, however,
seems to allow for moderate variation without dramatic consequences on
the function of hemoglobin. His45 is replaced by glutamine in Hb Bari
(141800.0009) and by arginine in Hb Fort de France (141800.0034).
.0177
MOVED TO 141850.0062
.0178
HEMOGLOBIN CAEN
HBA1, VAL132GLY
Wajcman et al. (1993) discovered the Hb Caen variant in a 25-year-old
French Caucasian woman suffering from a mild chronic hemolytic anemia.
Trypsin degradation of the isolated hemoglobin alpha chain followed by
high performance liquid chromatography indicated that the valine residue
at position 132 was replaced by glycine.
.0179
HEMOGLOBIN YUDA
HBA1, ALA130ASP
Hb Yuda was discovered in a 65-year-old Japanese female with
noninsulin-dependent diabetes mellitus (Fujisawa et al., 1992). Gas
phase Edman degradation indicated that the abnormal hemoglobin alpha
chain has a substitution of aspartic acid for alanine at residue 130. Hb
Yuda has a very low oxygen affinity and slightly decreased cooperative
subunit interaction.
.0180
HEMOGLOBIN CAPA
HBA1, ASP94GLY
Hb Capa was discovered in a 28-year-old female in Turkey who was being
treated for chronic iron deficiency anemia. The hemoglobin showed
abnormal electrophoretic mobility and was mildly unstable in a heat
denaturation test. The molecular change was a GAC-to-GGC transition in
codon 94, resulting in substitution of glycine for aspartic acid. Three
other substitutions of asp-94 are known: Hb Setif (141800.0130), Hb
Titusville (141800.0148), and Hb Sunshine Seth (141800.0143). All 4
variants exhibit mild instability.
.0181
HEMOGLOBIN MONTEFIORE
HBA1, ASP126TYR
Wajcman et al. (1992) demonstrated an asp126-to-tyr change in the HBA1
gene in an individual of Puerto Rican descent. At physiologic pH (7.4),
the oxygen binding of the patient's red blood cells revealed a 40%
reduction. Hb Montefiore appears to have lower cooperativity than other
characterized alpha-126 mutants: aspartic acid is replaced by asparagine
in Hb Tarrant (141800.0146), by histidine in Hb Sassari (141800.0126),
and by valine in Hb Fukutomi (141800.0163).
.0182
HEMOGLOBIN ROUEN
HEMOGLOBIN ETHIOPIA
HBA1, TYR140HIS
A tyr140-to-his mutation in the HBA1 gene was discovered and
characterized in a French patient with polycythemia vera by Wajcman et
al. (1992) and in a newborn baby of Ethiopian descent by Webber et al.
(1992). This mutation provides an example of an alteration of the
C-terminus of the alpha chain, a region involved in the mechanisms of
allosteric regulation. Hb Rouen has increased oxygen affinity and
decreased cooperativity. A complementary tyr145-to-his mutation (Hb
Bethesda; 141900.0022) in the hemoglobin beta chain has more dramatic
effects, suggesting that the alpha and beta chains play unequal roles in
the overall function of hemoglobin.
.0183
HEMOGLOBIN MELUSINE
HBA1, PRO114SER
Hb Melusine was found in an Algerian patient during a systematic
screening for hemoglobinopathies in Luxembourg. Using isoelectric
focusing and reverse phase high performance liquid chromatography
(RP-HPLC), Wajcman et al. (1993) determined that the molecular mutation
at amino acid position 114 of the HBA1 gene changed the residue from
proline to serine.
.0184
HEMOGLOBIN TAYBE
HBA1, THR38DEL OR THR39DEL
Girodon et al. (1992) reported the characterization of Hb Taybe, a
hemoglobin variant discovered in a young Arabic woman suffering since
birth from a severe and highly regenerative hemolytic anemia. DNA
amplification and sequencing of the HBA1 gene indicated a 3-bp deletion
(encoding threonine) at amino acid position 38 or 39. This variant
increases the hydrophobicity of the amino acid chain, and it is quite
unstable.
.0185
HEMOGLOBIN CEMENELUM
HBA1, ARG92TRP
Wajcman et al. (1994) described a missense mutation involving the same
codon as that involved in Hb Chesapeake (141800.0018), the first high
oxygen affinity hemoglobin variant to be described in association with
polycythemia (Charache et al., 1966). Hb Chesapeake has an arg92-to-leu
substitution; Hb Cemenelum has an arg92-to-trp substitution. Hb J (Cape
Town) (141800.0063) has a substitution (arg92-to-gln) in the same codon.
Hb Cemenelum was discovered in a French diabetic patient with no
hematologic abnormalities. The purified abnormal hemoglobin, like Hb J
(Cape Town), displayed only a 1.5- to 2-fold increased oxygen affinity.
The findings demonstrate that the degree to which the functional
properties are altered by changes in key residues at the alpha-beta
interface depends upon the specific residue occupying this position.
.0186
HEMOGLOBIN RAMONA
HBA1, TYR24CYS
Hb Ramona was accidentally detected by isoelectrofocusing in a pregnant
woman of part Spanish descent; its mobility was slightly faster than
that of Hb A. A TAT-to-TGT change was found at codon 24, corresponding
to a replacement of tyrosine by cysteine.
.0187
HEMOGLOBIN TATRAS
HBA1, LYS7ASN
In a 72-year-old woman born in Czechoslovakia, Wajcman et al. (1994)
found a lys7-to-asn mutation when investigating the basis for an
abnormal level of Hb A1c. No abnormal hematologic features were
observed.
.0188
HEMOGLOBIN LISBON
HBA1, GLU23ASP
In a 31-year-old man of Portuguese origin who had suffered from diabetes
mellitus since the age of 15 years, Wajcman et al. (1994) found an
abnormal hemoglobin during measurement of Hb A1c by an
isoelectrofocusing study. There were no abnormal hematologic features.
.0189
HEMOGLOBIN ROANNE
HBA1, ASP94GLU
Kister et al. (1995) described a new hemoglobin variant in a 73-year-old
woman from Roanne in central France. She suffered from mild chronic
hemolytic anemia. An asp94-to-glu substitution was found in the alpha-1
chain. Aspartate-94 is involved in several contacts, both in the deoxy-
and oxy-structures of the hemoglobin.
.0190
HEMOGLOBIN MALHACEN
HBA1, ALA123SER
Kazanetz et al. (1995) observed this variant hemoglobin in an adult male
in Granada, Spain, who was evaluated because of severe iron deficiency
anemia. Sequencing of the HBA1 gene showed 2 nucleotide changes. One was
a simple polymorphism, as both GCG and GCT code for alanine (at codon
120). The second mutation was a GCC-to-TCC change at codon 123 resulting
in replacement of alanine by serine. The replacement caused slight
differences in the IEF and reversed-phase HPLC experiments, but the
stability of the hemoglobin was normal. Family studies were not
performed; thus, whether the 2 mutations were in coupling or repulsion
was not known.
.0191
HEMOGLOBIN TUNIS-BIZERTE
HBA1, LEU129PRO
In 3 members of a Tunisian family, Darbellay et al. (1995) identified a
leu129-to-pro substitution in the HBA1 gene by sequencing the entirety
of the HBA2 and HBA1 genes. In the heterozygous state, the variant was
manifested by microcytosis, whereas the homozygous state showed moderate
anemia with marked microcytosis.
.0192
MOVED TO 141850.0068
.0193
HEMOGLOBIN BOIS GUILLAUME
HBA1, ALA65VAL
By tiny abnormalities observed during isoelectrofocusing, Wajcman et al.
(1995) identified this electrophoretically silent variant in 3 members
of a Caucasian-French family. This hemoglobin was the first alpha-chain
variant that involved position 64. In the beta chain, the corresponding
position, E14, is also occupied by an alanine residue; in Hb Seattle
(141900.0256), it is replaced by aspartic acid (ala70-to-asp).
.0194
HEMOGLOBIN MANTES-LA-JOLIE
HBA1, ALA79THR
Wajcman et al. (1995) found this variant hemoglobin during a systematic
study of the iron status in a 6-month-old baby and his mother who
originated from Chad in North Central Africa.
.0195
HEMOGLOBIN MOSELLA
HBA1, ALA111THR
Wajcman et al. (1995) found this variant in a 35-year-old pregnant woman
of Caucasian origin who lived in Luxembourg. The abnormal Hb was also
found in one of her daughters.
.0196
HEMOGLOBIN FUCHU-I
HBA1, HIS72TYR
At the Fuchu Municipal Medical Center in Tokyo, Harano et al. (1995)
identified 2 Hb variants in the course of assaying glycated hemoglobin,
Hb A(1c), of the peripheral blood by cation exchange HPLC. Structural
analyses demonstrated that 1 patient had a his72-to-tyr substitution and
the other an asn97-to-his substitution (141800.0197) of the alpha-globin
chain. These were named Hb Fuchu-I and Hb Fuchu-II, respectively. Both
were healthy adults.
.0197
HEMOGLOBIN FUCHU-II
HBA1, ASN97HIS
See 141800.0196.
.0198
HEMOGLOBIN GOUDA
HBA1, HIS72GLN
In a 54-year-old Dutch woman under treatment for diabetes mellitus,
Giordano et al. (1996) incidentally found a silent alpha-chain variant
on testing for glycated hemoglobin. A CAC-to-CAA transversion was
predicted to result in substitution of glutamine for histidine at
residue 72 in the HBA1 gene.
.0199
HEMOGLOBIN J (BISKRA)
HBA1, 24-BP DEL
Wajcman et al. (1998) described Hb J-Biskra, a variant hemoglobin
consisting of deletion of 24 nucleotides from the HBA1 gene and 8 amino
acid residues from the alpha-globin chain: residues 50-57, 51-58, or
52-59. This variant was mildly unstable in vitro only, and there was no
hematologic or biochemical evidence of hemolysis in affected family
members. Wajcman et al. (1998) stated that this was the largest deletion
reported to that time in a hemoglobin molecule that is expressed at an
almost normal level in the red blood cell.
.0200
HEMOGLOBIN GODAVARI
HBA1, PRO95THR
Hb Godavari is the fourth example of a substitution involving neutral
residues at position 95 of the alpha-1 chain. In all of these variants,
the electrophoretic pattern suggested that the structural modification
unmasks a charged residue in the alpha-1/beta-2 contact area. The other
examples are Hb Denmark Hill, pro95 to ala (141800.0027); Hb G
(Georgia), and pro95 to leu (141800.0038). Hb Godavari shared the same
electrophoretic properties as these variants, but displayed minimal
alterations of the oxygen-binding properties. Wajcman et al. (1998)
identified Hb Godavari in 2 families of different ethnic origin. The
first case, found in the Netherlands, involved an Indian patient. The
second case was identified a few months later in an African family from
Mali, living in France.
.0201
HEMOGLOBIN OITA
HBA1, HIS45PRO
Hamaguchi et al. (1998) reported a neutral (silent) hemoglobin variant,
designated Hb Oita, in which a change from CAC to CCC caused a
his45-to-pro substitution. In Hb Bari (141800.0009), his45 is replaced
by gln. In Hb Fort de France (141800.0034), his45 is replaced by arg. In
Hb Portiers (141800.0176), his45 is replaced by asp.
.0202
HEMOGLOBIN AGHIA SOPHIA
HBA1, VAL62DEL
In a Greek child with Hb H disease, Traeger-Synodinos et al. (1999)
found deletion of codon 62 of the alpha-1 gene, leading to
alpha-plus-thalassemia. Codon 62 encodes a valine residue at the E11
alpha helix, which is located in the interior of the heme pocket.
Substitutions of this valine with other amino acid residues in the alpha
as well as beta polypeptide chains lead, in the heterozygous carrier,
either to Hb M disease or to congenital nonspherocytic hemolytic anemia.
Traeger-Synodinos et al. (1999) assumed that deletion of val at position
62 disrupted the conformation of the alpha chain to such an extent that
the mutated subunit was rapidly removed by proteolysis. The final result
was an alpha-thalassemia phenotype rather than an unstable hemoglobin
syndrome. This conclusion was supported by the apparent absence of an
abnormal alpha chain in the peripheral blood of the patient. Hb Evans
(141850.0006) is a val62-to-met mutation of the HBA2 gene and was found
in a patient with mild hemolytic anemia. Four amino acid substitutions
at position 67(E11)val of the beta chain lead to instability of the Hb
tetramer and an anemia of variable degrees in the heterozygotes. One of
these substitutions, val67 to glu (141900.0163), results in the stable
Hb M-Milwaukee-I.
.0203
HEMOGLOBIN CHAROLLES
HBA1, HIS103TYR
Lacan et al. (1999) detected Hb Charolles in a 46-year-old patient who
presented with microcytosis and hypochromia. It was easily detected by
isoelectrofocusing and high performance liquid chromatography. It
accounted for 11% of the total hemoglobin. The amino acid change
resulted from a CAC-to-TAC change in codon 103.
.0204
HEMOGLOBIN ROUBAIX
HBA1, VAL55LEU
In a French family from the north of France, Prehu et al. (1999) found a
new HBA1 variant in 5 members. The variant was initially detected during
measurement of glycated hemoglobin in a woman originating from Roubaix.
Codon 55 in exon 2 was found to have a heterozygous change from GTT
(val) to CTT (leu). This was a neutral variant.
.0205
HEMOGLOBIN DOUALA
HBA1, SER3PHE
In a woman from Cameroon, Prehu et al. (2001) identified a new
hemoglobin variant, designated Hb Douala, with a C-to-T transition
(TCT-TTT) in the HBA1 gene, resulting in a ser3-to-phe (S3F) amino acid
substitution. The patient was also heterozygous for Hb S (141900.0243)
and for a 3.7-kb deletional alpha-thalassemia.
.0206
THALASSEMIA, ALPHA-PLUS
HBA1, 21-BP INS-DUP
In a patient of Iranian descent with the hematologic profile of
alpha-plus-thalassemia characterized by mild microcytosis, Waye et al.
(2001) found a 21-bp insertion/duplication that gave rise to a predicted
alpha-globin chain containing a duplication of amino acid residues
93-99.
.0207
THALASSEMIA, ALPHA-PLUS
HBA1, 33-BP DEL
In a patient of Greek descent with the hematologic profile of
alpha-plus-thalassemia characterized by mild microcytosis, Waye et al.
(2001) found a 33-bp deletion in the HBA1 gene resulting in a predicted
alpha-globin chain missing amino acid residues 64-74.
.0208
HEMOGLOBIN DELFZICHT
HBA1, ASN9LYS
Harteveld et al. (2002) reported a 69-year-old Dutch woman monitored for
diabetes mellitus in whom Hb A(L1c) analysis revealed a clinically
silent hemoglobin variant, asn9 to lys (N9K), due to an AAC-to-AAG
transversion in heterozygous state. The mutation was identical to that
found at the same position in the HBA2 gene that leads to a variant
named Hb Park Ridge (141850.0048).
.0209
HEMOGLOBIN SARATOGA SPRINGS
HBA1, LYS40ASN
In a 34-year-old Caucasian male of Swedish ancestry who lived in
Saratoga Springs, New York, Hoyer et al. (2003) identified a hemoglobin
variant with abnormal oxygen affinity, designated Hb Saratoga Springs.
There was no family history of erythrocytosis. The patient had no
smoking history. A change of codon 40 of the HBA1 gene from AAG to AAC
resulted in a lys40-to-asn (K40N) change. Lys40 is replaced by glu in Hb
Kariya (141800.0081), and by met in Hb Kanagawa (141800.0169). Both of
these hemoglobins had been shown to have increased oxygen affinity, but
neither was associated with erythrocytosis.
.0210
HEMOGLOBIN DIE
HBA1, VAL93ALA
In a 7-year-old girl living near the town of Die in southeast France,
Lacan et al. (2004) identified a val93-to-ala (V93A) mutation in the
HBA1 gene. The family was of French Caucasian origin.
.0211
HEMOGLOBIN BEZIERS
HBA1, LYS99ASN
In a 72-year-old woman of French Caucasian origin living in the city of
Beziers in the south of France, Lacan et al. (2004) identified a
lys99-to-asn (K99N) mutation in the HBA1 gene. The variant was found
during the determination of Hb A(1c) by high performance liquid
chromatography (HPLC) in this diabetic patient. Hematologic data were
normal, without hepatomegaly or splenomegaly.
.0212
HEMOGLOBIN BUFFALO
HBA1, HIS89GLN
In a 32-year-old Somali male living in the Netherlands who was being
monitored for diabetes mellitus, Harteveld et al. (2004) identified Hb S
(141900.0243) in heterozygous state and a heterozygous C-to-G
transversion in the HBA1 gene, resulting in a his89-to-gln (H89Q)
substitution. The H89Q mutation had previously been described in a
Yemenite woman and 2 apparently unrelated Somali males (Hoyer et al.,
2002), and had been designated Hb Buffalo. No hematologic abnormality
had been associated with the allelic variant in this or other cases. In
addition to Hb Buffalo, 4 amino acid substitutions had been reported at
codon 89: Hb Luton (his89 to leu; 141800.0172), Hb Villeurbanne (his89
to tyr; 141800.0213), Hb Tokyo (his89 to pro; 141800.0214), and Hb
Tamano (his89 to arg; 141800.0215).
.0213
HEMOGLOBIN VILLEURBANNE
HBA1, HIS89TYR
Deon et al. (1997) identified a his89-to-tyr (H89Y) mutation in the HBA1
gene as the defect in Hb Villeurbanne.
.0214
HEMOGLOBIN TOKYO
HBA1, HIS89PRO
Harteveld et al. (2004) stated that Hb Tokyo carries a his89-to-pro
(H89P) mutation in the HBA1 gene.
.0215
HEMOGLOBIN TAMANO
HBA1, HIS89ARG
Harteveld et al. (2004) stated that Hb Tamano carries a his89-to-arg
(H89R) mutation in the HBA1 gene.
.0216
HEMOGLOBIN RICCARTON
HBA1, GLY51SER
In a 4-year-old Caucasian boy investigated for fatigue and microcytosis,
Brennan et al. (2005) found a GGC-to-AGC transition at codon 51 in the
HBA1 gene, resulting in a gly51-to-ser substitution (G51S). The mutation
was thought not to be the cause of the microcytosis as it was detected
also in the boy's father who had normal red cell indices.
.0217
HEMOGLOBIN OEGSTGEEST
HBA1, CYS104SER
In an 8-year-old black female of Surinamese origin with a mild
alpha-thalassemia phenotype, Harteveld et al. (2005) identified
homozygosity for a TGC-to-AGC transversion in the HBA1 gene, resulting
in a cys104-to-ser substitution. Cysteine-104 is involved in alpha/beta
globin contact and had been described as a critical amino acid of the
HBA2 chain when substituted by a tyrosine (cys104 to tyr) in Hb
Sallanches (141850.0031).
.0218
HEMOGLOBIN LAMEN ISLAND
HBA1, 149709T-C
De Gobbi et al. (2006) studied 148 individuals from Melanesia with
alpha-thalassemia, including 5 with HbH disease, in whom none of the
theretofore described molecular defects could be found. The pattern of
inheritance suggested that individuals with HbH disease were homozygous
for a codominant defect, referred to as (alpha-alpha)T, causing
alpha-thalassemia with a predicted genotype of
(alpha-alpha)T/(alpha-alpha)T. In situ RNA hybridization in erythroid
cells from an affected individual from Lamen Island (Vanuatu) detected
substantially fewer nuclear transcripts from the alpha-globin genes than
from the beta-globin genes. DNA FISH in 2 affected individuals showed
that the alpha-globin cluster was present at its normal location of
chromosome 16, and no deletions or chromosomal rearrangements were
detected in any of these individuals. Linkage analysis showed that the
disease phenotype in individuals was derived from telomeric chromosome
16 T. Only the C allele of SNP195 (C or T, located at coordinate 149709)
segregated with thalassemia in the affected families and showed complete
association with the (alpha-alpha)T haplotype. This allele was not found
in a separate analysis of 131 nonthalassemic Melanesian individuals.
SNP195 changes the sequence 5-prime-TAATAA-3-prime (T allele) to
5-prime-TGATAA-3-prime (C allele), potentially creating a new binding
site for the key erythroid transcription factor GATA1. GATA1 binds at
the C allele of SNP195 in vivo. SNP195 creates a new promoter-like
element between the upstream regulatory elements and their cognate
promoters. This element, when activated, causes significant
downregulation of the alpha-D, alpha-2, and alpha-1 genes that lie
downstream, thereby causing alpha-thalassemia.
.0219
ALPHA-THALASSEMIA
HBA1, 1-BP DEL, 354C
In a newborn of mixed black and Chinese descent who carried the
Southeast Asian alpha-0-thal deletion, Eng et al. (2006) also found a
1-bp deletion of cysteine from codon 78 in exon 2 of the HBA1 gene,
resulting in a frameshift and premature termination at codon 83.
.0220
HEMOGLOBIN AUCKLAND
HBA1, HIS87ASN
In a 27-year-old woman with mild compensated hemolytic anemia, Brennan
and Matthews (1997) identified Hb Auckland, a his87-to-asn substitution
in the HBA1 gene.
.9999
HEMOGLOBIN ALPHA VARIANTS, MOLECULAR DEFECT UNKNOWN
HEMOGLOBIN J (INDIA). See Raper (1957).
HEMOGLOBIN J (MALAYA). See Lehmann (1962).
HEMOGLOBIN K (CALCUTTA). Fast hemoglobin. See Lehmann (1962).
HEMOGLOBIN K (MADRAS). See Ager and Lehmann (1957).
HEMOGLOBIN KARAMOJO. See Allbrook et al. (1965).
HEMOGLOBIN L (BOMBAY). See Sukumaran and Pik (1965).
HEMOGLOBIN M (RESERVE). Reduced oxygen affinity and decreased reversible
oxygen-binding capacity (Overly et al., 1967).
HEMOGLOBIN N, ALPHA TYPE. An alpha chain anomaly was deduced from
molecular hybridization experiments with canine hemoglobin (Silvestroni
et al., 1963). Other hemoglobin N variants have a beta change.
HEMOGLOBIN NICOSIA. See Fessas et al. (1965).
See Also:
Al-Awamy et al. (1985); Baklouti et al. (1988); Barg et al. (1982);
Barton et al. (1982); Brittenham et al. (1980); Davis et al. (1979);
Dincol et al. (1994); Dozy et al. (1979); Embury et al. (1979); Harano
et al. (1983); Harano et al. (1983); Harano et al. (1983); Harano
et al. (1984); Harano et al. (1982); Hess et al. (1983); Higgs et
al. (1981); Hill et al. (1985); Huisman and Miller (1976); Kan et
al. (1979); Kielman et al. (1993); Li et al. (1990); Liang et al.
(1981); Liebhaber et al. (1980); Marinucci et al. (1979); Meloni et
al. (1980); Ohba et al. (1978); Phillips et al. (1979); Phillips et
al. (1980); Pobedimskaya et al. (1994); Priest et al. (1989); Proudfoot
and Maniatis (1980); Romao et al. (1992); Schroeder and Jones (1965);
Shimizu et al. (1965); Southern (1975); Vella et al. (1974); Wainscoat
et al. (1983); Wajcman et al. (1989); Wajcman et al. (1990); Wajcman
et al. (1992); Wajcman et al. (1992); Wajcman et al. (1993); Wajcman
et al. (1990); Weatherall and Clegg (1979); Zimmer et al. (1980)
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Najman, A.; Reman, O.; Leporrier, M.; Galacteros, F.: Unstable alpha-chain
hemoglobin variants with factitious beta-thalassemia biosynthetic
ratio: Hb Questembert (alpha131 [H14] ser-to-pro) and Hb Caen (alpha132
[H15] val-to-gly). Am. J. Hemat. 42: 367-374, 1993.
406. Wajcman, H.; Vasseur, C.; Galacteros, F.; Blouquit, Y.; Rosa,
J.; Labie, D.; Najman, A.: Hb Questembert [alpha-131(H14)ser-to-pro]:
a new highly unstable variant with unbalanced chain synthesis. (Abstract) Blood 76
(suppl. 1): 79a, 1990.
407. Waye, J. S.; Eng, B.; Patterson, M.; Carcao, M. D.; Chang, L.;
Olivieri, N. F.; Chui, D. H. K.: Identification of two new alpha-thalassemia
mutations in exon 2 of the alpha-1-globin gene. Hemoglobin 25: 391-396,
2001.
408. Weatherall, D. J.; Clegg, J. B.: Recent developments in the
molecular genetics of human hemoglobin. Cell 16: 467-479, 1979.
409. Webber, B. B.; Lam, H.; Wilson, J. B.; Huisman, T. H. J.: Hb
Albany-GA or alpha11(A9)lys-to-asn. Hemoglobin 7: 257-262, 1983.
410. Webber, B. B.; Wilson, J. B.; Gu, L.-H.; Huisman, T. H. J.:
Hb Ethiopia or alpha140(HC2)tyr-to-his. Hemoglobin 16: 441-443,
1992.
411. Weitkamp, L. R.; Stamatoyannopoulos, G.; Rowley, P. T.; Kirk,
R. L.: The linkage relationships of the haemoglobin beta, delta and
alpha loci with 34 genetic marker systems. Ann. Hum. Genet. 41:
61-75, 1977.
412. Wilkie, A. O. M.; Higgs, D. R.; Rack, K. A.; Buckle, V. J.; Spurr,
N. K.; Fischel-Ghodsian, N.; Ceccherini, I.; Brown, W. R. A.; Harris,
P. C.: Stable length polymorphism of up to 260 kb at the tip of the
short arm of human chromosome 16. Cell 64: 595-606, 1991.
413. Williamson, D.; Langdown, J. V.; Myles, T.; Mason, C.; Henthorn,
J. S.; Davies, S. C.: Polycythaemia and microcytosis arising from
the combination of a new high oxygen affinity haemoglobin (Hb Luton,
alpha-89 his-to-leu) and alpha-thalassaemia trait. Brit. J. Haemat. 82:
621-622, 1992.
414. Wilson, J. T.; deRiel, J. K.; Forget, B. G.; Marotta, C. A.;
Weissman, S. M.: Nucleotide sequence of 3-prime untranslated portion
of human alpha globin mRNA. Nucleic Acids Res. 4: 2353-2368, 1977.
415. Wiltshire, B. G.; Clark, K. G. A.; Lorkin, P. A.; Lehmann, H.
: Haemoglobin Denmark Hill (alpha 95 (G2) pro-to-ala), a variant with
unusual electrophoretic and oxygen-binding properties. Biochim. Biophys.
Acta 278: 459-464, 1972.
416. Winter, W. P.; Rucknagel, D. L.; Fielding, J.: Identification
of several rare hemoglobin variants discovered in a population survey
including a new variant Hb Garden State alpha-82 ala-to-asp. (Abstract) Clin.
Res. 26: 122A, 1978.
417. Wong, S. C.; Ali, M. A. M.; Pond, J. R.; Rubin, S. M.; Johnson,
S. E. N.; Wilson, J. B.; Huisman, T. H. J.: Hb J-Singa (alpha-78
asn-to-asp), a newly discovered hemoglobin variant with the same amino
acid substitution as one of the two present in Hb J-Singapore (alpha-78
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1984.
418. Yamaoka, K.; Kawamura, K.; Hanada, M.; Seita, M.; Hitsumoto,
S.; Ooya, I.: Studies on abnormal haemoglobins. Jpn. J. Hum. Genet. 5:
99-111, 1960.
419. Yanase, T.; Hanada, M.; Seita, M.; Ohya, I.; Ohta, Y.; Imamura,
T.; Fujimura, T.; Kawasaki, K.; Yamaoka, K.: Molecular basis of morbidity
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J. Hum. Genet. 13: 40-53, 1968.
420. Yi, C. H.; Li, H. J.; Li, H. W.; Zhang, X. S.; Zhao, X. N.; Zhang,
C. T.: Hemoglobin Shenyang found among Uygurs in P.R. China. Hemoglobin 13:
97-99, 1989.
421. Yi-Tao, Z.; Headlee, M. E.; Henson, J.; Lam, H.; Wilson, J. B.;
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422. Yodsowan, B.; Svasti, J.; Srisomsap, C.; Winichagoon, P.; Fucharoen,
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423. Yongsuwan, S.; Svasti, J.; Fucharoen, S.: Decreased heat stability
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Q-Thailand (alpha74 (EF3) asp-to-his): gene organization, molecular
structure, and DNA diagnosis. Hemoglobin 16: 481-491, 1992.
425. Zeng, Y.; Huang, S.; Liang, X.; Long, G.; Lam, H.; Wilson, J.
B.; Huisman, T. H. J.: Hb Wuming or alpha11 (A9) lys-to-gln. Hemoglobin 5:
679-687, 1981.
426. Zeng, Y.; Huang, S.; Qiu, X.; Cheng, G.; Ren, Z.; Jin, Q.; Chen,
C.; Jiao, C.; Tang, Z.; Liu, R.; Bao, X.; Zeng, L.; Duan, Y.; Zhang,
G.: Hemoglobin Chongqing (alpha2 (NA2) leu-to-arg) and hemoglobin
Harbin (alpha16 (A14) lys-to-met) found in China. Hemoglobin 8:
569-581, 1984.
427. Zeng, Y.; Huang, S.; Zhou, X.; Qiu, X.; Dong, Q.; Li, M.; Bai,
J.: Hb Shenyang (alpha26 (B7) ala-to-glu): a new unstable variant
found in China. Hemoglobin 6: 625-628, 1982.
428. Zhao, W.; Wilson, J. B.; Webber, B. B.; Kutlar, A.; Tamagnini,
G. P.; Kuam, B.; Huisman, T. H. J.: Hb Hekinan observed in three
Chinese from Macau: identification of the GAG-to-GAT mutation in the
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429. Zhou, Z.; Chen, L.; Chen, P.; Zhang, K.; Wang, Y.: Hemoglobin
Hangzhou alpha64 (E13) asp-to-gly: a new variant found in China. Hemoglobin 11:
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Hb Port Huron (alpha56(E5)lys-to-arg): a new alpha chain variant. Hemoglobin 15:
381-391, 1991.
Clinical Synopsis:
Heme:
Alpha polypeptide hemoglobin chain;
Alpha-thalassemia silent carrier (3 normal genes);
Alpha-thalassemia with microcytosis (2 normal genes);
Alpha-thalassemia with microcytosis and hemolysis, Hb H disease (1
normal gene);
Alpha-thalassemia with fatal Hb Bart's hydrops fetalis (No normal
gene);
Polycythemia (e.g. Hb Chesapeake .0018);
Unstable hemoglobin (e.g. Hb Contaldo .0022);
Hemolysis (e.g. Hb Koelliker .0083);
Methemoglobinemia (e.g. Hb M Boston .0092);
Amelioration of SS disease (e.g. Hb Memphis .0096);
Congenital Heinz body anemia (e.g. Hb Toyama .0152)
Skin:
Jaundice;
Cyanosis
Misc:
Two alpha-globin genes: 5-prime or alpha-2 and 3-prime or alpha-1)
Lab:
Decreased heme-heme interaction (e.g. Hb Kanagawa .0169);
Increased oxygen affinity (e.g. Hb Nunobiki .0109);
Reduced oxygen affinity (e.g. Thionville .0168);
Decreased reversible oxygen-binding capacity (e.g. Hb L (Bombay) .9999)
Inheritance:
Autosomal dominant (16p13.33 to 16p13.11)
Contributors:
Patricia A. Hartz - updated: 01/28/2010
Carol A. Bocchini - updated: 5/22/2009
Victor A. McKusick - updated: 9/19/2006
Ada Hamosh - updated: 7/21/2006
Victor A. McKusick - updated: 3/29/2006
Victor A. McKusick - updated: 10/11/2005
Victor A. McKusick - updated: 8/11/2005
Victor A. McKusick - updated: 5/11/2005
Victor A. McKusick - updated: 12/6/2004
Victor A. McKusick - updated: 8/6/2004
Victor A. McKusick - updated: 6/2/2004
Victor A. McKusick - updated: 1/20/2004
Victor A. McKusick - updated: 1/15/2004
Victor A. McKusick - updated: 9/2/2003
Victor A. McKusick - updated: 3/5/2003
Victor A. McKusick - updated: 10/2/2002
Victor A. McKusick - updated: 6/3/2002
Victor A. McKusick - updated: 5/23/2002
Victor A. McKusick - updated: 2/27/2002
Victor A. McKusick - updated: 11/1/2001
Victor A. McKusick - updated: 10/11/2001
Victor A. McKusick - updated: 5/1/2000
Victor A. McKusick - updated: 1/19/2000
Victor A. McKusick - updated: 7/14/1999
Ada Hamosh - updated: 4/21/1999
Victor A. McKusick - updated: 2/24/1999
Victor A. McKusick - updated: 2/9/1999
Ada Hamosh - updated: 6/12/1998
Victor A. McKusick - updated: 4/30/1998
Victor A. McKusick - updated: 2/6/1998
Victor A. McKusick - updated: 8/27/1997
Creation Date:
Victor A. McKusick: 6/23/1986
Edit Dates:
alopez: 01/28/2010
terry: 6/3/2009
carol: 5/22/2009
terry: 1/15/2009
terry: 1/14/2009
wwang: 10/4/2007
wwang: 10/3/2006
terry: 9/19/2006
alopez: 7/25/2006
terry: 7/21/2006
terry: 6/23/2006
terry: 3/29/2006
carol: 10/21/2005
wwang: 10/21/2005
terry: 10/11/2005
carol: 10/3/2005
terry: 8/11/2005
wwang: 6/7/2005
terry: 5/17/2005
wwang: 5/13/2005
terry: 5/11/2005
terry: 2/7/2005
tkritzer: 1/25/2005
terry: 12/6/2004
tkritzer: 8/10/2004
terry: 8/6/2004
tkritzer: 6/8/2004
terry: 6/2/2004
carol: 3/17/2004
tkritzer: 1/21/2004
terry: 1/20/2004
terry: 1/15/2004
cwells: 9/3/2003
terry: 9/2/2003
carol: 8/29/2003
carol: 8/25/2003
carol: 5/13/2003
terry: 4/17/2003
terry: 3/5/2003
terry: 3/3/2003
tkritzer: 12/10/2002
tkritzer: 10/7/2002
tkritzer: 10/3/2002
tkritzer: 10/2/2002
carol: 6/3/2002
terry: 6/3/2002
terry: 5/23/2002
cwells: 3/22/2002
cwells: 3/20/2002
terry: 2/27/2002
mcapotos: 11/1/2001
mcapotos: 10/26/2001
mcapotos: 10/11/2001
cwells: 5/31/2001
mcapotos: 2/19/2001
mcapotos: 2/15/2001
terry: 2/14/2001
mcapotos: 5/26/2000
mcapotos: 5/24/2000
terry: 5/1/2000
mcapotos: 2/7/2000
mcapotos: 2/4/2000
carol: 1/28/2000
mcapotos: 1/28/2000
mcapotos: 1/24/2000
terry: 1/19/2000
carol: 12/8/1999
mgross: 7/16/1999
terry: 7/14/1999
carol: 6/27/1999
terry: 4/30/1999
alopez: 4/21/1999
terry: 3/24/1999
carol: 3/9/1999
terry: 2/24/1999
mgross: 2/16/1999
mgross: 2/11/1999
terry: 2/9/1999
dkim: 7/21/1998
carol: 7/2/1998
alopez: 6/12/1998
terry: 6/5/1998
alopez: 5/14/1998
carol: 5/4/1998
terry: 4/30/1998
mark: 2/16/1998
terry: 2/6/1998
mark: 10/19/1997
jenny: 9/5/1997
terry: 8/27/1997
alopez: 7/31/1997
alopez: 7/29/1997
terry: 7/10/1997
mark: 7/10/1997
alopez: 7/10/1997
terry: 7/9/1997
terry: 7/7/1997
mark: 6/14/1997
terry: 11/15/1996
terry: 11/13/1996
mark: 4/12/1996
terry: 4/9/1996
mark: 2/13/1996
terry: 2/5/1996
mark: 11/17/1995
terry: 11/18/1994
jason: 7/29/1994
pfoster: 4/25/1994
mimadm: 4/17/1994
warfield: 4/8/1994
OMIM
