Database: OMIMEntry: 306700
LinkDB: 306700
MIM Entry: 306700
Title:
+306700 HEMOPHILIA A
;;HEMOPHILIA, CLASSIC; HEMA
COAGULATION FACTOR VIII, INCLUDED; F8, INCLUDED;;
COAGULATION FACTOR VIIIC, PROCOAGULANT COMPONENT, INCLUDED; F8C, INCLUDED
Text:
DESCRIPTION
Hemophilia A is an X-linked, recessive, bleeding disorder caused by a
deficiency in the activity of coagulation factor VIII. Affected
individuals develop a variable phenotype of hemorrhage into joints and
muscles, easy bruising, and prolonged bleeding from wounds. The disorder
is caused by heterogeneous mutations in the factor VIII gene which maps
to Xq28. Despite the heterogeneity in factor VIII mutations, carrier
detection and prenatal diagnosis can be done by direct detection of
selected mutations (especially the inversions), as well as indirectly by
linkage analysis. Replacement of factor VIII is done using a variety of
preparations derived from human plasma or recombinant techniques. While
replacement therapy is effective in most cases, 10 to 15% of treated
individuals develop neutralizing antibodies that decrease its
effectiveness.
NOMENCLATURE
The term hemophilia is used in reference to hemophilia A (factor VIII
deficiency); hemophilia B or Christmas disease (factor IX deficiency)
and von Willebrand disease (von Willebrand factor deficiency). Whereas
hemophilia A and B are X-linked disorders, von Willebrand disease has an
autosomal dominant, or in some cases, an autosomal recessive mode of
inheritance.
PHENOTYPE
Affected individuals develop a variable phenotype of hemorrhage into
joints and muscles, easy bruising, and prolonged bleeding from wounds. A
partial deficiency in heterozygous carriers was demonstrated by Rapaport
et al. (1960). Hemophilia A and B are clinically similar and can only be
distinguished by assays of factor VIII and factor IX (F9; 300746)
activity. In contrast von Willebrand disease more often presents with
mucocutaneous or gastrointestinal hemorrhage or menorrhagia. Tests used
in its diagnosis include bleeding time, platelet aggregation, and factor
VIII and von Willebrand factor assays.
CLINICAL FEATURES
The severity and frequency of bleeding in hemophilia A is inversely
related to the amount of residual factor VIII (<1%, severe; 2-5%,
moderate; and 5-30%, mild). The proportion of cases that are severe,
moderate, and mild are about 50, 10, and 40%, respectively, see
Antonarakis et al. (1995). The joints (ankles, knees, hips, and elbows)
are frequently affected causing swelling, pain, decreased function, and
degenerative arthritis. Similarly, muscle hemorrhage can cause necrosis,
contractures, and neuropathy by entrapment. Hematuria occurs
occasionally and is usually painless. Intracranial hemorrhage, while
uncommon, can occur after even mild head trauma and lead to severe
complications. Bleeding from tongue or lip lacerations is often
persistent.
Rosendaal et al. (1990) presented evidence supporting their earlier
findings that mortality due to ischemic heart disease is lower in
hemophilia patients than in the general male population.
- Female Carriers
In a population-based survey in the Netherlands, Plug et al. (2006)
found that female carriers of hemophilia A and B (HEMB; 306900) bled
more frequently than noncarrier women, especially after medical
procedures, such as tooth extraction or tonsillectomy. Reduced clotting
factor levels correlated with a mild hemophilia phenotype. Variation in
clotting levels was attributed to lyonization.
BIOCHEMICAL FEATURES
Hemophilia A is the result of a hereditary defect in antihemophilic
globulin (factor VIII). It is a complex of a large inert carrier protein
and a noncovalently bound small fragment which contains the procoagulant
active site. While Zacharski et al. (1968) showed that leukocytes
(probably lymphocytes) synthesize some factor VIII in vitro, it is
synthesized primarily in the liver. Cooper and Wagner (1974) presented
evidence that the carrier molecule is normally present in the plasma of
hemophilia A patients and Fay et al. (1982) isolated a highly purified
human factor VIII that consisted of a single high molecular weight
polypeptide chain having the highest specific activity. The factor VIII
complex, with a molecular weight in excess of 1 million, has 2
components: (1) factor VIII (molecular weight of 293,000 ) called factor
VIII C, when measured by procoagulant activity and factor VIII Ag, when
measured immunologically and (2) factor VIII R (the von Willebrand
factor or vWF) has a molecular weight of 220,000. Polymerization leads
to the high molecular weight of the factor VIII complex (Levin, 1979).
Factor VIII is encoded by the factor VIII gene on Xq28 while the vWF
which affects bleeding time and ristocetin aggregation of platelets is
encoded by a gene on chromosome 12.
Alexander and Goldstein (1953) first noted low levels of factor VIII in
cases of von Willebrand disease (193400). This was confirmed by other
workers including Nilsson et al. (1957), who studied von Willebrand's
original family in the Aland Islands. Thus, an autosomal locus can also
cause low factor VIII levels. This overlap in phenotype between
hemophilia A and von Willebrand disease is seen in families such as that
of Graham et al. (1953) and Bond et al. (1962) in which the carrier
females showed depression of factor VIII levels, not as low as in
hemizygous affected males and sometimes clinical hemophilia.
Pratt et al. (1999) reported the crystal structure of the human factor
VIII C2 domain at a resolution of 1.5 angstroms. The structure reveals a
beta-sandwich core, from which 2 beta-turns and a loop display a group
of solvent-exposed hydrophobic residues. Behind the hydrophobic surface
lies a ring of positively charged residues. This motif suggests a
mechanism for membrane binding involving both hydrophobic and
electrostatic interactions. The structure explains, in part, mutations
in the C2 region of factor VIII that lead to bleeding disorders in
hemophilia A.
OTHER FEATURES
Among 4 patients with hemophilia A, Feinstein et al. (1969) found that
the plasma of 2 showed no neutralizing activity with a human antibody to
factor VIII. The plasma from the other 2 had neutralizing activity
comparable to that of controls. Using neutralization of a factor-VIII
inhibitor as a measure of cross-reacting material in the plasma of
hemophiliacs, Denson (1968) found that 33 hemophilic plasmas (presumably
from separate patients) showed little neutralization, whereas 3
hemophilic plasmas showed about the same neutralization as controls
indicating the CRM-positive and CRM-negative forms of hemophilia. Hoyer
and Breckenridge (1968) also found heterogeneity in hemophilia A.
Frommel et al. (1977) studied 10 sibships of hemophilia A, each of which
included 1 or 2 hemophilic brothers with antibody to factor VIII. Their
results suggested linkage of the MHC (142800) and a gene responsible for
an immune response to isolygous factor VIII. The development of factor
VIII antibodies has been interpreted in terms of CRM-positivity versus
CRM-negativity by others (Boyer et al., 1973). For hemophilia A and B 2
subtypes exist--one without any immunologically demonstrable protein and
one with immunologically normal but hemostatically defective protein
(Denson et al., 1969).
Stites et al. (1971) were able to detect factor VIII immunologically in
all of 14 patients with hemophilia A they studied, whereas little or no
factor VIII was identified in patients with von Willebrand disease.
Zimmerman et al. (1971) found immunoreactive material in all of 22
patients with hemophilia A. Allotype of factor VIII has been
demonstrated by human but not animal antisera (Stites et al., 1971).
An acquired disorder resembling hemophilia A is sometimes caused by the
development by autoantibodies against factor VIII (Nilsson and Lamme,
1980; Zimmerman et al., 1971). Rheumatoid arthritis is one of the
disorders in which autoantibodies to factor VIII may develop.
Most heterozygous female carriers of hemophilia A or hemophilia B have
concentrations of clotting factor VIII or IX of about 50% of normal,
respectively, and in most cases have mildly decreased coagulability
without clinical signs. Sramek et al. (2003) followed up a cohort of
1,012 mothers of all known people with hemophilia in the Netherlands
from birth to death, or the end-of-study date (41,984 person years of
follow-up). Overall mortality was decreased by 22%. Deaths from ischemic
heart disease were reduced by 36%. No decrease in mortality was observed
for cerebral stoke (ischemic and hemorrhagic combined). Women in the
cohort had an increased risk of deaths from extra cranial hemorrhage;
however, the number of deaths from this cause was much lower than that
for ischemic heart disease. The results were interpreted as showing that
a mild decrease in coagulability has a protective effect against fatal
ischemic heart disease.
Chronic synovitis occurs in about 10% of Indian patients with severe
hemophilia. Ghosh et al. (2003) reported an association between the
development of chronic synovitis in patients with hemophilia and the
HLA-B27 allele (142830.0001). Twenty-one (64%) of 33 patients with both
disorders had HLA-B27, compared to 23 (5%) of 440 with severe hemophilia
without synovitis (odds ratio of 31.6). There were 3 sib pairs with
hemophilia in whom only 1 sib had synovitis; all the affected sibs had
the HLA-B27 allele, whereas the unaffected sibs did not. Chronic
synovitis presented as swelling of the joint with heat and redness and
absence of response to treatment with factor concentrate. Ghosh et al.
(2003) suggested that patients with HLA-B27 may not be able to easily
downregulate inflammatory mediators after bleeding in the joints,
leading to chronic synovitis.
GENOTYPE
While Vogel (1977) concluded that the mutation rate causing hemophilia A
is higher in males than in females Barrai et al. (1979) did not.
Brocker-Vriends et al. (1991) estimated that the mutation rate in males
is 5.2 times that in females (95% confidence interval 1.8 to 15.1)
suggesting that the probability of carriership for mothers of an
isolated case amounts to 86%. Although this would imply that 14% of the
mothers are not carriers in the classical sense, they may be mosaic for
the mutation and, therefore, at risk of transmitting the mutation more
than once. While Hermann (1966) reported an age effect on the mutation
rate in hemophilia, Barrai et al. (1968) concluded that there was no
effect of maternal age or maternal grandfather's age (at the birth of
the patient's mother). Subsequently, from RFLP analysis in families with
sporadic hemophilia A, Bernardi et al. (1987) found data consistent with
a higher mutation rate in males than in females. Based on carrier
detection tests of 21 mothers of isolated cases of severe hemophilia A,
Winter et al. (1983) derived a maximum likelihood estimate of 9.6 (95%
confidence limits 2.2-41.5) for the ratio of male to female mutation. A
similar male mutation preponderance has been found for the Lesch-Nyhan
syndrome (308000) but not for Duchenne muscular dystrophy (310200).
Rosendaal et al. (1990) collected information by mail on 462 Dutch
patients with severe or moderately severe hemophilia A. Pedigree
analysis on 189 of these patients who were the first hemophiliacs in
their family showed, by the maximum likelihood method, that the ratio of
mutation frequencies in males and females was 2.1, with a 95% confidence
interval of 0.7-6.7.
In a review, Antonarakis et al. (1995) collected the findings of more
than 1,000 hemophilia subjects examined for factor VIII gene mutations.
These include point mutations, inversions, deletions, and unidentified
mutations which constitute 46%, 42%, 8%, 4%, and 91%, 0%, 0%, and 9%,
respectively, of those with severe versus mild to moderate disease,
respectively, in selected studies. The 266 point mutations described as
of April, 1994 comprised missense (53%), CpG-to-TpG (16%), small
deletions (12%), nonsense (9%), small inversions and splicing (3% each),
and missense polymorphisms and silent mutations in exons (2% each). In
addition to these point mutations 100 different larger deletions and 9
insertion mutations had been reported. Inversion mutations resulting
from recombinations between DNA sequences in the A gene in intron 22 of
the factor VIII gene and 1 of 2 other A genes upstream to factor VIII
have been shown to cause a large portion of cases.
Data on more than 2,000 samples suggested that the common inversion
mutations are found in 42% of all severe hemophilia A subjects. Whereas
98% of the mothers of those with inversions were carriers of the
inversion, only about 1 de novo inversion was found in maternal cells
for every 25 mothers of sporadic cases; see Antonarakis et al. (1995).
When the maternal grandparental origin of inversions was examined the
ratio of de novo occurrences in male:female germ cells was 69:1.
Brinke et al. (1996) reported the presence of a novel inversion in 2
hemophilic monozygotic twins. These patients showed an inversion that
affects the first intron of the F8 gene, displacing the most telomeric
exon (exon 1) of F8 further towards the telomere and close to the C6.1A
gene (BRCC3; 300617). Brinke et al. (1996) noted that this novel
inversion creates 2 hybrid transcription units. One of these is formed
by the promoter and first exon of F8 and widely expressed sequences that
map telomeric to the C6.1A sequence. The other hybrid transcription unit
contains the CpG island and all of the known sequence of C6.1A and the
3-prime section of most of the F8 gene.
Regarding those with inhibitors, a variety of factor VIII gene mutations
have been found. Of the 30 cases reviewed, 87 and 13% had different
nonsense and missense mutations, respectively; see Antonarakis et al.
(1995). Finally, factor VIII gene inversions do not seem to be a major
predisposing factor for the development of inhibitors. Of severe
hemophilia A cases 16% of those without and 20% of those with inversions
develop inhibitors; see Antonarakis et al. (1995).
Schwaab et al. (1995) found that the probability of developing factor
VIII inhibitors is greater in patients with large deletions in the
factor VIII gene. Factor VIII inhibitors neutralize factor VIII
procoagulant activity by sterically preventing the interaction of factor
VIII with von Willebrand factor, phospholipids, activated factor IX,
thrombin, and activated factor X. Another mechanism for inactivation of
factor VIII is the proteolysis of factor VIII by anti-factor VIII
antibodies. Lacroix-Desmazes et al. (2002) found significant proteolytic
activity in IgG from 13 of 24 inhibitor-positive patients. No hydrolytic
activity was detected in control antibodies of IgG from patients without
inhibitors. The relationship between hydrolytic activity of IgG and
factor VIII-neutralizing activity was not consistent. Antibodies from
some patients caused hydrolysis of factor VIII at low rates, but the
plasma had strong inhibitory activity; in other cases, the IgG caused
hydrolysis of factor VIII at high rates, but the plasma had weak
inhibitory activity; in yet other samples, there were high rates of both
hydrolysis and inhibitory activity.
Viel et al. (2009) sequenced the factor VIII gene in 78 black patients
with hemophilia to identify the causative mutations and background
haplotypes, which the authors designated H1 to H5. They found that 24%
of the patients had a H3 or H4 haplotype, and that the prevalence of
inhibitors was higher among patients with either of those haplotypes
than among patients with haplotypes H1 or H2 (odds ratio, 3.6; p =
0.04), despite a similar spectrum of hemophilic mutations and degree of
severity of illness in the 2 subgroups. Noting that Caucasians carry
only the H1 or H2 haplotypes and that most blood donors are Caucasian,
Viel et al. (2009) suggested that mismatched factor VIII replacement
therapy might be a risk factor for the development of anti-factor VIII
alloantibodies.
INHERITANCE
Hemophilia A is an X-linked recessive disorder whose locus (factor VIII)
has been mapped to Xq28. Using improved methods of carrier detection,
Biggs and Rizza (1976) studied 41 mothers of sporadic cases of
hemophilia A and found that 39 were in fact carriers. In addition,
Rosendaal et al. (1990) performed a meta-analysis of all published
studies on the sex ratio of mutation frequencies. From pooling of 6
studies, they estimated that mutations originate 3.1 times more often in
males than in females (95% confidence interval 1.9-4.9). This implies
that 80% of mothers of an isolated patient are expected to be hemophilia
carriers. This estimate of prior risk is required for the application of
Bayes theorem to probability calculations in carriership testing.
Vidaud et al. (1989) presented evidence that a case of apparent
transmission of hemophilia from father to son was due to uniparental
disomy. Gamete complementation, involving fertilization of a nullisomic
oocyte by a disomic sperm carrying both an X and a Y, was thought to
have occurred. More than 15 X-linked DNA markers indicated that the
son's X chromosome was inherited from his father. Nisen and Waber (1989)
studied X-chromosome inactivation patterns as indicated by DNA
methylation in 3 families with hemophilic daughters. One was a case of
severe hemophilia B in a girl referred to in 306900. The other 2 were
cases of hemophilia A. First, the maternal and paternal X chromosomes
were distinguished by RFLPs. Second, patterns of methylation of selected
genes on the X-chromosome were determined using methylation-sensitive
restriction endonucleases. Of the 6 X-chromosome probes tested, only the
PGK (311800) and HPRT (308000) clones were informative. After digestion
with HpaII or HhaI, the hybridization intensity of the RFLPs of all 3
mothers and an unaffected sister were diminished by 50%, consistent with
random X-chromosome inactivation. The methylation patterns of the X
chromosomes of the affected females, however, were clearly nonrandom.
Depending on the probe and the patient, HPRT and PGK sequences were
either completely methylated or unmethylated. Thus, nonrandom
X-chromosome inactivation was the basis for severe hemophilia in these
females.
Females can be affected, i. e., Pola and Svojitka (1957) reported a
homozygous affected female who was the daughter of a hemophilic man
married to a double first cousin and Sie et al. (1985) reported a
homozygous female. In these cases, the homozygous female is no more
severely affected than the hemizygous male. Hemophilia A can occur in
females because of inheritance of defective factor VIII genes from both
parents (e.g., Pola and Svojitka, 1957), or on the basis of an autosome
translocation disrupting the structure of the gene (e.g., Migeon et al.,
1989). Theoretically, a female can be homozygous on the basis of
uniparental isodisomy. It is also possible, in some cases diagnosed as
hemophilia A, that actually von Willebrand disease (193400) is producing
the hemorrhagic diathesis with very low levels of factor VIII. Coleman
et al. (1993) reported yet another unusual mechanism for full-blown
hemophilia A in a female, namely, biased X inactivation. A female infant
born to a mother with incontinentia pigmenti (IP) and a father with
hemophilia A manifested both disorders. Methylation studies of
peripheral blood DNA from the infant, her mother, and 2 female relatives
with IP showed a highly skewed pattern of X inactivation. Random
patterns were observed in the infant's 2 sisters, who did not have IP
and had the usual carrier activity of factor VIII. Coleman et al. (1993)
postulated that the usual negative selection against cells with the
IP-bearing X chromosome as the active one had unmasked the factor VIII
mutation on the infant's other X chromosome. Thus, the infant was
functionally hemizygous for the factor VIII mutation inherited from the
father.
Windsor et al. (1995) described yet another mechanism for severe
hemophilia A in a female: the presence of 2 de novo factor VIII
mutations, an X chromosome deletion, and a paternal F8 inversion
mutation. Neither parent showed evidence of the mutation in somatic DNA.
CYTOGENETICS
Samama et al. (1977) confirmed assignment of the hemophilia A locus to
the long arm by demonstration of hemophilia in a girl whose mother was a
carrier and one of whose X chromosomes had partial deletion of the long
arm. By in situ hybridization, Tantravahi et al. (1986) concluded that
HEMA is located in the proximal part of Xq28 with probes DX13 and St14
distally located. Using a hybrid cell line that contains only a terminal
Xq28 fragment, Tantravahi et al. (1986) found that HEMA probes did not
hybridize but the DX13 and St14 did hybridize to the DNA of that cell
line.
MAPPING
Linkage studies in the early 1960s indicated that hemophilia A and B
(306900) are not allelic (McKusick, 1964). The independence of the 2
loci was confirmed when Robertson and Trueman (1964) found a family in
which both hemophilia A and hemophilia B were segregating; one male was
deficient in both factor VIII and factor IX. From study of another
family in which both hemophilia A and hemophilia B were segregating,
Woodliff and Jackson (1966) concluded that the 2 loci are far apart.
Direct studies of linkage between hemophilias A and B in the dog
indicated that the 2 loci are at least 50 map units apart (Brinkhous et
al., 1973). Haldane and Smith (1947) concluded that there is 5-20%
recombination between the CDB and hemophilia loci with the most probable
value about 10%. Smith (1968) subsequently concluded that the data on
which the estimate was based were heterogeneous, with some families
(presumably hemophilia A) showing very close linkage and others
(presumably hemophilia B) showing no linkage. In black families, Boyer
and Graham (1965) demonstrated close linkage of hemophilia A and the A/B
polymorphism of G6PD (305900). Filippi et al. (1984) stated that 58
scorable sibs, all nonrecombinant for the linkage of HEMA and G6PD, were
known by that time. From this, they inferred that the 90% upper limit of
meiotic recombination between the 2 loci is <4%.
G6PD (305900) is one of the 5 rather tightly linked loci located on
Xq28, the others being CBD (303800), CBP (303900), HEMA, and ALD
(300371). In a physical map of the most distal 12 Mb of Xq, Poustka et
al. (1991) found that the factor VIII gene lies about 1.1 Mb from the
telomere, with G6PD proximal to it, and about 1.5 Mb from the telomere.
This contradicts the earlier impression that the gene is located in the
proximal part of Xq28. In the case of a 9-year-old Malaysian female with
de novo hemophilia A as well as a complex de novo translocation
involving one X chromosome and one chromosome 17 (Muneer et al., 1986),
Migeon et al. (1993) identified a breakpoint within Xq28 with deletion
of the 5-prime end of the factor VIII gene, leaving the more proximal
G6PD locus intact on the derivative chromosome 17. As the deleted
segment included the 5-prime half of F8C as well as the subtelomeric
DXYS64 locus, they concluded that factor VIII is oriented on the
chromosome with its 5-prime region closest to the telomere.
Patterson et al. (1987) showed that the G6PD and factor VIII genes lie
within 500 kb of each other. Arveiler et al. (1989) showed that G6PD and
factor VIII are in the same 290-kb pulsed field gel electrophoresis
fragment they did not establish which of the genes is more proximal.
Kenwrick and Gitschier (1989) established the order:
cen--R/GCP--GDX--G6PD--F8--DXS15--tel. The direction of transcription of
the GDX, G6PD, and factor VIII genes is toward the centromere, i.e., the
R/GCP end of the region. Patterson et al. (1989) showed that the genomic
sequences recognized by the anonymous probe 767 (DXS115) are localized
to 2 sites within Xq28. One site lies within intron 22 of the factor
VIII gene. The second site, which contains the RFLPs detected by 767, is
located within 1.2 megabases of the factor VIIII gene. Genetic data
indicate tight linkage of factor VIII and DXS115; maximum lod = 8.30 at
theta = 0.04. The evidence that G6PD is located in the Xq28 region is
outlined in 305900.
Harper et al. (1984) did linkage studies with the DNA probe DX13, which
had been localized to band Xq28. When DNA is digested with the
restriction enzyme BglII, the probe recognizes an RFLP for which 50% of
females are heterozygous. No recombination was observed between the HEMA
and DX13 loci. The workers concluded that the marker is useful for
carrier detection and prenatal diagnosis. About 30% recombination was
found between the factor VIII and IX loci. Oberle et al. (1985) observed
very close linkage of a polymorphic anonymous DNA probe called St14
(from Strasbourg, France). No recombination (theta=0) was found in 12
families (lod score 9.65). The probe is informative in more than 90% of
families and can be used in conjunction with assays of factor VIII to
identify carriers with 96% confidence or better. St14 can be used for
prenatal diagnosis of disorders such as hemophilia A and
adrenoleukodystrophy because of close linkage (Oberle et al., 1985).
Janco et al. (1987) used the more accurate intragenic factor VIII RFLPs
to detect hemophilia A carriers.
MOLECULAR GENETICS
Ratnoff and Bennett (1973) reviewed the genetics of coagulation
disorders emphasizing CRM+ and CRM- varieties. McGinniss et al. (1993)
reported that half of hemophilia A patients have no detectable factor
VIII; about 5% have normal levels of dysfunctional factor VIII as
protein and are termed CRM-+, whereas the rest ( 45%) have plasma factor
VIII Ag protein reduced to an extent roughly comparable to the level of
factor VIIIC activity and are designated CRM-reduced. They found in an
analysis of mutations that almost all CRM-positive/reduced mutations
(24/26) were missense, and many (12/26) occurred at CpG dinucleotides.
They showed that 18 of 19 amino acid residues altered by mutation in
these patients were conserved in the porcine and murine sequences.
Almost half of the mutations (11/26) were clustered in the A2 domain. In
studies in hemophilia families, Antonarakis et al. (1985) identified
several molecular defects. One family had a deletion of about 80 kb in
the factor VIII gene. Another family had a single nucleotide change in
the coding region of the gene producing a nonsense codon leading to
premature termination of factor VIII synthesis. In addition, they used 2
common polymorphic sites in the factor VIII gene to differentiate the
normal gene from the defective gene in 4 of 6 obligate carriers from
families with patients in whom inhibitors did not develop. In both the
family with a large deletion and the family with premature termination
of factor VIII synthesis, affected persons developed inhibitors. Human
intron 22 is hypomethylated on the active X and methylated on the
inactive X. Inaba et al. (1990) described an MspI RFLP in intron 22 of
the factor VIII gene. Japanese showed 45% heterozygosity and Asian
Indians showed 13%; polymorphism was not found in American blacks or
Caucasians.
In a study of 83 patients with hemophilia A, Youssoufian et al. (1986)
identified 2 different point mutations, one in exon 18 and one in exon
22, that recurred independently in unrelated families. Each mutation
produced a nonsense codon by a change of CG to TG. In the opinion of
Youssoufian et al. (1986), these observations indicated that CpG
dinucleotides are mutation hotspots. It has been postulated that
methylated cytosines may be mutation hotspots because 5-methylcytosine
can spontaneously deaminate to thymine, resulting in a C-to-T transition
in DNA. Barker et al. (1984) found an unusually high frequency of
polymorphism at a number of loci in human DNA using restriction enzymes
whose recognition sequences contain a CpG dinucleotide. None of the 83
patients with partial gene deletions studied by Youssoufian et al.
(1987) had circulating inhibitors. The authors demonstrated that 1
deletion occurred de novo in a germ cell of the maternal grandmother,
while a second deletion occurred in a germ cell of a maternal
grandfather. Thus, de novo deletions of X-linked genes can occur in
either male or female gametes. Gitschier et al. (1986) found that the
normal arginine codon number 2307 was converted to a stop codon in a
severe hemophiliac with no detectable factor VIIIC activity (see
306700.0001). In a mild hemophiliac with 10% of normal activity, the
same codon was converted to glutamine (see 306700.0042). In the first
case, the CGA which codes for arginine was converted to TGA, which codes
for a stop. In the second case, CGA was changed to CAA, which codes for
glutamine. A diminished level of factor VIII Ag in the latter patient
coincided with the level of clotting activity, suggesting that the
abnormal factor VIII was relatively unstable. Pecorara et al. (1987)
reported a relatively large experience with carrier detection and
prenatal diagnosis by means of RFLPs. Youssoufian et al. (1988) screened
240 patients with hemophilia A and found CG to TG transitions in an exon
in 9. They identified novel missense mutations leading to severe
hemophilia A and estimated that the extent of hypermutability of CpG
dinucleotides is 10 to 20 times greater than the average mutation rate
for hemophilia A.
In a case of hemophilia A, Youssoufian et al. (1987) described the first
instance of insertional mutagenesis in man. They identified a long
inserted element (LINE) in the factor VIII gene; see Kazazian et al.
(1988). L1 (LINE-1) sequences are a human-specific family of long,
interspersed, repetitive elements, present in about 100,000 copies
dispersed throughout the genome. The full-length L1 sequence is 6.1
kilobases, but most L1 elements are truncated at the 5-prime end,
resulting in a 5-fold higher copy number of 3-prime sequences. Kazazian
et al. (1988) found insertions of L1 elements into exon 14 of the factor
VIII gene in 2 of 240 unrelated patients with hemophilia A. Both of
these insertions (3.8 and 2.3 kb, respectively) contained 3-prime
portions of the L1 sequence. They interpreted these results as
indicating that certain L1 sequences in man can be dispersed, presumably
by an RNA intermediate, and cause disease by insertional mutation. Both
of the above insertions were de novo events, appearing either during
embryogenesis in the patient or in the mother's germ cells. The L1
element transposed into one of these patients was demonstrated by
Dombroski et al. (1991) to have come from a retrotransposable element
located on chromosome 22 (see 151626). Woods-Samuels et al. (1989)
characterized a third L1 insertion in intron 10 of the factor VIII of a
hemophilia A patient. This L1 insertion was not a cause of hemophilia in
the patient because it was also present in the maternal grandfather, who
did not have the disease. Altogether the L1 insertion was present in 4
generations of the family. All 3 of the L1 insertions discovered by
Dombroski et al. (1991) have open reading frames (ORFs), and the 3
derived amino acid sequences are 98 to 99% identical. They show
similarity in the sequence of the L1 3-prime ORFs, and the polymerase
domain of reverse transcriptase was observed in all 3 L1 insertions. The
presence of ORFs and the close sequence similarity of these recently
inserted L1 elements provide indirect evidence for the existence of a
set of functional L1 elements that encodes 1 or more proteins necessary
for their retrotransposition.
Higuchi et al. (1988) found deletion of about 2,000 bases spanning exon
3 and part of IVS3 in a patient with severe hemophilia A. The mother was
judged to be a somatic mosaic because the defective gene could be
identified in only a portion of the leukocytes and cultured fibroblasts.
By use of a cDNA probe corresponding to exons 14-26 of factor VIII,
Bardoni et al. (1988) studied 49 Italian patients with severe hemophilia
A. They found no TaqI site mutations but did find a partial deletion,
eliminating exons 15-18 and spanning about 13 kb, in a patient with
anti-factor VIII antibodies. Howard et al. (1988) showed that the mother
of a hemophilic boy carried a mutation in the X chromosome she received
from her nonhemophilic father rather than in the X chromosome received
from her mother. Thus, the father was a gonadal mosaic. In studies of a
sporadic case of hemophilia, Gitschier (1988) found that the mother had
partial duplication of the factor VIII gene. Among her 7 children, in
addition to the hemophilic male who had partial deletion of factor VIII,
there were some who inherited her normal X chromosome and others who
inherited her duplicated X chromosome. Possibly the duplication in the
mother predisposed to deletion. Youssoufian et al. (1988) reported 6
other partial factor VIII gene deletions in severe hemophilia A,
bringing to 12 the number of deletions among 240 patients. No
association was observed between the size or location of deletions and
the presence of inhibitors to factor VIII. Furthermore, no 'hotspots'
for deletion breakpoints were identified.
Since point mutations in the factor VIII gene are responsible for most
cases of hemophilia A and only a small proportion of these mutations can
be recognized by restriction endonuclease analysis, Traystman et al.
(1990) used PCR and denaturing gradient gel electrophoresis (DGGE) to
characterize single nucleotide substitutions. A GC clamp was attached to
the 5-prime PCR primer to allow detection of most single base changes in
DNA fragments ranging in size from 249 to 356 bp. (A 'GC clamp' is a
sequence rich in G and C such that it is relatively resistant to melting
by heating, see Myers et al., 1985 and Abrams et al., 1990.) Ten of 11
known point mutations were definitively separated. Traystman et al.
(1990) then used these methods, applied to exon 8, the 3-prime end of
exon 14, exon 17, exon 18, and exon 24, in a study of 52 patients with
unknown mutations. A 'new' disease-producing mutation was found in 2 of
the patients: a missense mutation in exon 14 (tyr-to-cys at amino acid
residue 1709), and a missense mutation in exon 18 (asn-to-asp at amino
acid residue 1922). A previously described mutation in exon 24
(arg-to-gln at amino acid residue 2209) was found in a third patient. In
addition, a new polymorphic nucleotide substitution was found in intron
7. Traystman et al. (1990) detected all of these mutations when the
GC-clamped products from all 5 regions were run in the same denaturing
gel. Kogan and Gitschier (1990) likewise used DGGE to identify mutations
and found a DNA polymorphism, located in intron 7, which they thought
might be useful for genetic prediction in cases in which the BclI and
XbaI polymorphisms are uninformative. In studies of 83 unrelated Finnish
patients with hemophilia A, Levinson et al. (1990) identified specific
mutations, falling into 3 classes, in 10 patients: 5 mutations caused
loss of TaqI restriction sites; 1 point mutation resulted in a new TaqI
site; and 4 represented partial gene deletions. Although exons 5 and 6
were involved in 3 of the 4 partial gene deletions, the extent of the
DNA loss differed in each. The fourth deletion was located entirely
within intron 1. There was no history of hemophilia in 8 of the 10
families. The origin of the mutation was determined in 6 of these
pedigrees, 2 of which showed evidence for maternal mosaicism.
Brocker-Vriends et al. (1990) described a case of hemophilia A due to
partial deletion of the factor VIII gene of about 2 kb, spanning exon 5
and part of introns 4 and 5; the mother was a somatic and presumably
gonadal mosaic for the mutation although coagulation assays and RFLP
analysis in the family did not suggest a carrier status.
Higuchi et al. (1991) pointed out that whereas nearly all mutations
resulting in mild to moderate hemophilia B can be detected by PCR and
denaturing gradient gel electrophoresis (DGGE), these methods sufficed
in only of 16 of 30 (53%) patients with severe hemophilia A. They
interpreted this to indicate that the mutations in DNA sequence lay
outside the regions studied and may include locus-controlling regions,
other sequences within introns or outside the gene that are important
for its expression, or perhaps another gene involved in factor VIII
expression that is very closely linked to the factor VIII gene. Higuchi
et al. (1991) designed a total of 45 primer sets to amplify 99% of the
coding region of the F8C gene and 41 of 50 splice junctions. After PCR
amplification they used denaturing gradient gel electrophoresis (DGGE)
to identify successfully the point mutations in 26 DNAs with different
previously identified changes. Among 29 patients with unknown mutations,
they identified the disease-producing change in 25 (86%). Two
polymorphisms and 2 rare normal variants were also found. Naylor et al.
(1992) used an mRNA-based method to examine hemophilia A mutations and
were able to explain the report of Higuchi et al. (1991) that mutations
could not be identified in 14 of 30 severely affected patients although
mutations were found in all but 1 of 17 less severely affected patients.
Naylor et al. (1992) found an unusual cluster of mutations involving
regions of intron 22 not examined earlier and leading to defective
joining of exons 22 and 23 in the mRNA as the cause of hemophilia A in
10 of 24 severely affected UK patients. These results confirmed
predictions about the efficacy of the method suggested by Naylor et al.
(1991) and also excluded hypotheses proposing that mutations outside the
factor VIII gene are responsible for a large proportion of severe
hemophilia A.
Levinson et al. (1990) found a curious example of a gene within a gene.
In looking for transcripts from the Xq28 region, they found one referred
to as the A gene that hybridized to a region in exon 22 of the factor
VIII gene. The A or F8A gene (305423) was in reverse orientation to
factor VIII and was contained entirely in intron 22. Computer analysis
of the sequence suggested that the A gene encodes a protein, with the
complication that codon usage analysis suggested a frameshift halfway
through the gene. The A gene cDNA also bound to mouse, monkey, and rat
genomic DNA in a 'zoo blot.' The mouse A gene was also found to be on
the X chromosome but not within the mouse factor VIII gene as it is in
the human. Freije and Schlessinger (1992) demonstrated that the X
chromosome contains 3 copies of F8A and its adjacent regions, 1 in
intron 22 and 2 telomeric and upstream to the factor VIII gene
transcription start site. Gene F8A, which is transcribed in the opposite
direction to factor VIII, is intronless and completely nested within
intron 22. Approximately 500 kb upstream of the factor VIII gene, there
are 2 additional transcribed copies of the F8A gene. Lakich et al.
(1993) pointed out that intron 22 is unusual in many respects. At 32 kb,
it is the largest intron in the factor VIII gene. It also contains a CpG
island, located about 10 kb downstream of exon 22. This island appears
to serve as a bidirectional promoter for the F8A and F8B (305424) genes.
The F8B gene is also located in intron 22 and is transcribed in the
opposite direction from factor VIII; its first exon lies within intron
22 and is spliced to exons 23-26. The F8A and B genes are both expressed
ubiquitously.
Lakich et al. (1993) proposed that many of the previously unidentified
mutations resulting in severe hemophilia A are based on recombination
between the homologous F8A sequences within intron 22 and upstream of
the factor VIII gene. Such a recombination would lead to an inversion of
all intervening DNA and a disruption of the gene. Lakich et al. (1993)
presented evidence to support this model and described a Southern blot
assay that detects the inversion. They suggested that this assay should
permit genetic prediction of hemophilia A in approximately 45% of
families with severe disease. Of the 28 patients reported by Naylor et
al. (1993), 5 had mild or moderate disease and all had a missense
mutation. The other 23 patients were severely affected; unexpectedly,
intron 22 seemed to be the target of approximately 40% of the mutations
causing severe hemophilia A. Naylor et al. (1993) found that the basis
of the unique factor VIII mRNA defect that prevented PCR amplification
across the boundary between exons 22 and 23 was an abnormality in the
internal regions of intron 22. They showed that exons 1-22 of the factor
VIII mRNA had become part of a hybrid message containing new
multi-exonic sequences expressed in normal cells. The novel sequences
were not located in a YAC containing the whole factor VIII gene.
Southern blots from patients probed by novel sequences and clones
covering intron 22 showed no obvious abnormalities. Naylor et al. (1993)
also suggested that inversions involving intron 22 repeated sequences
are the basis of the mRNA defect. These mutations in severely affected
patients occur at the surprising rate of approximately 4 x 10(-6) per
gene per gamete per generation. Furthermore, it has been shown that
these de novo inversions occur more frequently in males than females
with a ratio of 302:1 estimated in male:female germ cells. Rossiter et
al. (1994) hypothesized that pairing of Xq with its homolog inhibits the
intrachromosomal inversion that is responsible for nearly half of all
cases of severe hemophilia A. This would predict that the event
originates predominantly in male germ cells. They presented findings
supporting the hypothesis: in all 20 informative cases in which the
inversion originated in a maternal grandparent, DNA polymorphism
analysis determined that it occurred in the male germline. In addition,
all but 1 of 50 mothers of sporadic cases due to an inversion were
carriers.
It is hypothesized that the inversion mutations occur almost exclusively
in germ cells during meiotic cell division by an intrachromosomal
recombination between a 9.6-kb sequence within intron 22 and 1 of 2
almost identical copies located about 300 kb distal to the factor VIII
gene at the telomeric end of the X chromosome. Most inversion mutations
originate in male germ cells, where the lack of bivalent formation may
facilitate flipping of the telomeric end of the single X chromosome.
Oldenburg et al. (2000) reported the first instance of intron 22
inversion presenting as somatic mosaicism in a female, affecting only
about 50% of lymphocyte and fibroblast cells of the proposita. Supposing
a postzygotic de novo mutation as the usual cause of somatic mosaicism,
the finding implies that the intron 22 inversion mutation is not
restricted to meiotic cell divisions but can also occur during mitotic
cell divisions, either in germ cell precursors or in somatic cells.
In a study of 147 sporadic cases of severe hemophilia A, Becker et al.
(1996) were able to identify the causative defect in the F8 gene in 126
patients (85.7%). An inversion of the gene was found in 55 patients
(37.4%), a point mutation in 47 (32%), a small deletion in 14 (9.5%), a
large deletion in 8 (5.4%), and a small insertion in 2 (1.4%). In 4
(2.7%), mutations were localized but not yet sequenced. No mutation was
identified in 17 patients (11.6%). The identified mutations occurred in
the B domain in 16 (10.9%); 4 of these were located in an adenosine
nucleotide stretch at codon 1192, indicating a mutation hotspot. Somatic
mosaicism was detected in 3 (3.9%) of 76 patients' mothers, comprising 3
of 16 de novo mutations in the patients' mothers. Investigation of
family relatives allowed detection of a de novo mutation in 16 of 76
2-generation and 28 of 34 3-generation families. On the basis of these
data, Becker et al. (1996) estimated the male:female ratio of mutation
frequencies (k) to be 3.6. By use of the quotients of mutation origin in
maternal grandfather to patients' mother or to maternal grandmother, k
values were directly estimated as 15 and 7.5, respectively. Considering
each mutation type separately, they found a mutation type-specific sex
ratio of mutation frequencies. Point mutations showed a
5-to-10-fold-higher and inversions a more than 10-fold-higher mutation
rate in male germ cells, whereas deletions showed a more than
5-fold-higher mutation rate in female germ cells. Consequently, and in
accordance with the data of other disorders such as Duchenne muscular
dystrophy, the results indicated to Becker et al. (1996) that at least
for X-chromosomal disorders the male:female mutation rate is determined
by its proportion of the different mutation types.
Having previously reported the existence of 5 CpG islands close to the
factor VIII gene, 4 of which they cloned by genomic walking, Gitschier's
group (Kenwrick et al., 1992) reported the isolation of the remaining
island, located approximately 70 kb telomeric of the 5-prime end of the
factor VIII gene. They identified cDNA clones corresponding to 2
transcribed sequences, C6.1A (BRCC3; 300617) and C6.1B (MTCP1; 300116),
that originate from this CpG island. The C6.1A gene was highly conserved
between species and expressed abundantly in many human and mouse
tissues. No striking homologies to existing genes could be found for
either sequence. Kenwrick et al. (1992) found that both genes were
deleted in 2 brothers who suffered from mental handicap and dysmorphism
as well as hemophilia A.
In a Japanese family with mild to moderately severe hemophilia A, Young
et al. (1997) found a deletion of a single nucleotide T within an
A(8)TA(2) sequence of exon 14 of the F8 gene. The severity of the
clinical phenotype did not correspond to that expected of a frameshift
mutation. A small amount of functional factor VIII protein was detected
in the patient's plasma. Analysis of DNA and RNA molecules from normal
and affected individuals and in vitro transcription/translation
suggested a partial correction of the molecular defect, because of the
following: (i) DNA replication/RNA transcription errors resulted in
restoration of the reading frame and/or (ii) 'ribosomal frameshifting'
resulted in the production of normal factor VIII polypeptide and, thus,
in a milder-than-expected hemophilia A. All of these mechanisms probably
were promoted by the longer run of adenines, A(10) instead of A(8)TA(2),
after the deleted T. Young et al. (1997) concluded that errors in the
complex steps of gene expression therefore may partially correct a
severe frameshift defect and ameliorate an expected severe phenotype.
Leuer et al. (2001) explored the hypothesis that a significant
proportion of de novo mutations causing hemophilia A can be attributed
to a germline or somatic mosaic originating from a mutation during early
embryogenesis. They used allele-specific PCR to analyze 61 families that
included members who had sporadic severe hemophilia A and known factor
VIII gene defects. The presence of somatic mosaicism of varying degrees
(0.2 to 25%) could be shown in 8 (13%) of the 61 families and was
confirmed by a mutation-enrichment procedure. All mosaics were found in
families with point mutations (8 of 32 families). In a subgroup of 8
families with CpG transitions, the percentage with mosaicism increased
to 50% (4 of 8 families). In contrast, no mosaics were observed in 13
families with small deletions or insertions or in 16 families with
intron 22 inversions. These data suggested that mosaicism may represent
a fairly common event in hemophilia A. As a consequence, risk assessment
in genetic counseling should include consideration of the possibility of
somatic mosaicism in families with apparently de novo mutations,
especially families with the subtype of point mutations.
Cutler et al. (2002) identified 81 mutations in the F8C gene in 96
unrelated patients, all of whom had previously typed negative for the
common IVS22 inversion mutation (306700.0067). Forty-one of these
mutations were not recorded in F8C gene mutation databases. Analysis of
these 41 mutations with regard to location, possible cross-species
conservation, and type of substitution, in correlation with the clinical
severity of the disease, supported the view that the phenotypic result
of a mutation in the F8C gene correlates more with the position of the
amino acid change within the 3-dimensional structure of the protein than
with the actual nature of the alteration.
Valleix et al. (2002) described monozygotic twin females who were
heterozygous for a tyr16-to-cys mutation in the F8C gene (Y16C;
306700.0269) which most probably arose in the paternal germline. Both
twins showed skewing of X inactivation toward the maternally derived
normal X chromosome, the most severely affected twin exhibiting a higher
percentage of inactivation of the normal X chromosome. The degree of
skewing of X inactivation closely correlated with both the coagulation
parameters and the clinical phenotype of the twins. Monozygotic twins
may be monochorionic or dichorionic, depending on whether they develop
in a single or 2 distinct chorionic sacs. Dichorionic twinning occurs
prior to or around the onset of X inactivation and monochorionic
twinning occurs later. A discordant X-inactivation pattern might
therefore be expected to be seen more frequently in dichorionic twins.
As these twins were monochorionic, Valleix et al. (2002) suggested that
the twinning event in this case may have been after the onset of X
inactivation.
Bicocchi et al. (2005) reported a 3-generation family in which 3 females
were affected with classic hemophilia A due to a heterozygous missense
mutation in the F8C gene. All 3 women showed completely skewed X
inactivation with expression only of the mutant gene in all tissues
analyzed, including leukocytes, skin fibroblasts, uroepithelium, and
buccal mucosa. Although no mutations were identified in the XIST gene
(314670), Bicocchi et al. (2005) determined that all 3 women had the
same XIST allele, and suggested that an alteration within the
X-inactivation center on the chromosome carrying the F8C mutation
prevented it from being inactivated.
Renault et al. (2007) described a 3-generation family segregating 2
distinct phenotypes, hemophilia A and dramatically skewed X chromosome
inactivation, the convergence of which led to the expression of
hemophilia A in 3 heterozygous females. All affected males and females
had a proximal (type II) IVS22 inversion of the F8 gene. No female
carried more than 1 inverted allele. The 3 affected females had skewed X
inactivation in favor of the mutant X; 3 unaffected females also had
skewed X inactivation, 2 in favor of the normal X, and the third did not
carry the mutation. Renault et al. (2007) stated that known causes of
skewing were not consistent with their findings in this family,
suggesting that the X chromosome inactivation ratios were genetically
influenced (see XCE, 300074).
The molecular diagnosis of hemophilia A is challenging because of the
high number of different causative mutations that are distributed
through the large F8 gene. The putative role of the novel mutations,
especially missense mutations, may be difficult to interpret as causing
hemophilia A. Guillet et al. (2006) identified 95 novel mutations out of
180 different mutations found among 515 patients with hemophilia A from
406 unrelated families followed up at a single hemophilia treatment
center in a Paris hospital. The 95 novel mutations comprised 55 missense
mutations, 12 nonsense mutations, 11 splice site mutations, and 17 small
insertions/deletions. They used a strategy in interpreting the causality
of novel F8 mutations based on a combination of the familial segregation
of the mutation, the resulting biologic and clinical hemophilia A
phenotype, and the molecular consequences of the amino acid
substitution. For the latter, they studied the putative biochemical
modifications: its conservation status with cross-species factor VIII
and homologous proteins, its putative location in known factor VIII
functional regions, and its spatial position in the available factor
VIII 3D structures.
Among 1,410 Italian patients with hemophilia A, Santacroce et al. (2008)
identified 382 different mutations in the F8 gene, 217 (57%) of which
had not previously been reported. Mutations leading to a null allele
accounted for 82%, 15%, and less than 1% of severe, moderate, or mild
hemophilia, respectively. Missense mutations were identified in 16%,
68%, and 81% of severe, moderate, or mild hemophilia, respectively,
yielding a good genotype/phenotype correlation useful for treatment and
genetic counseling.
In order to establish a national database of F8 mutations, Green et al.
(2008) identified and cataloged multiple mutations in approximately
one-third of the U.K. hemophilia A population. The risk of developing
inhibitors for patients with nonsense mutations was greater when the
stop codon was in the 3-prime half of the mRNA. The most common change
was the intron 22 inversion (306700.0067), which accounted for 16.6% of
all mutations and for 38% of those causing severe disease.
PATHOGENESIS
The clinical features of hemophilia A all result from the lack of factor
VIII despite the presence of all other coagulation factors and
platelets. Replacement by intravenous infusion of factor VIII restores
normal hemostasis during the time period that the infused factor remains
in physiologic concentrations in the circulation.
DIAGNOSIS
Kogan et al. (1987) modified the procedure of PCR to use a heat-stable
DNA polymerase which allowed the repeated rounds of DNA synthesis to
proceed at 63 degrees C. The high sequence specificity of PCR at this
temperature enabled detection of restriction-site polymorphisms,
contained in PCR products derived from clinical samples to be analyzed
by visual inspection of their digestion products on polyacrylamide gels.
Kogan et al. (1987) used the improved method to detect carriers of
hemophilia A and to diagnose hemophilia prenatally. Levinson et al.
(1987) used RNAse A cleavage and DNA sequencing of the altered region to
identify a mutation in the factor VIII gene in a case of hemophilia. The
mutation identified by Levinson et al. (1987) was a novel G-to-C
transversion which resulted in a missense mutation, with proline being
substituted for arginine in one of the active domains of the factor VIII
molecule. (Erlich et al. (1988) improved the PCR method using
thermostable DNA polymerase from Thermus aquaticus.) Cooper and
Youssoufian (1988) collated reports of single basepair mutations within
gene coding regions causing human genetic disease. They found that 35%
of mutations occurred within CpG dinucleotides. Over 90% of these
mutations were C-to-T or G-to-A transitions, which thus occur within
coding regions at a frequency 42-times higher than that predicted from
random mutation. Cooper and Youssoufian (1988) believed these findings
were consistent with methylation-induced deamination of 5-methylcytosine
and suggested that methylation of DNA within coding regions may
contribute significantly to the incidence of human genetic disease. Baty
et al. (1986) demonstrated how DNA diagnosis can be helpful in
obstetrical decisions and early care of hemophilia even though the
family does not make use of the information for elective abortion.
Specifically, Cesarean section was performed and the parents were
psychologically prepared.
Lavery (2008) described strategies for preimplantation genetic diagnosis
of hemophilia, including embryo sexing, specific mutation analysis,
coamplification of polymorphic markers, direct sequencing of F8, and
haplotyping after multiple displacement amplification, and discussed the
ethical challenges.
CLINICAL MANAGEMENT
The mainstay of routine treatment for hemophilia A is infusion of factor
VIII done using amounts that are required to restore the factor VIII
activity to therapeutic levels. Since the half-life of factor VIII is
8-12 hours, twice daily infusions may be required in some circumstances.
Desmopressin (dDAVP), a synthetic analog of the neurohypophyseal
nonapeptide arginine vasopressin (192340), has been approved for
treatment of mild hemophilia A and von Willebrand disease. Following
dDAVP in some cases concentrations of factor VIII and von Willebrand
factor are transiently increased to levels that allow minor surgery
(Richardson and Robinson, 1985).
Pignone et al. (1992) had success within induction of immune tolerance
in patients with hemophilia A and factor VIII inhibitors: combined
treatment with gammaglobulin, cyclophosphamide, and factor VIII. Nilsson
et al. (1988) used combined cyclophosphamide, intravenous IgG, and
factor VIII therapy to induce immune tolerance to factor VIII infusions
in patients with antibodies to factor VIII. Factor VIII coagulant
antibodies disappeared in 9 of 11 patients so treated; the other 2
patients did not respond. Earlier treatment with either factor VIII and
cyclophosphamide or factor VIII and IgG had been ineffective, suggesting
that all 3 components of the protocol are necessary for the successful
induction of tolerance.
Schwartz et al. (1990) used antihemophilic factor produced by
recombinant DNA methods in the successful treatment of hemophilia A in
107 subjects. The half-lives equaled or exceeded those of plasma-derived
factor VIII, and immunogenicity appeared to be no greater. This
represented a major advance because of the opportunity to avoid exposure
to transfusion-associated viral diseases. The factor VIII gene was first
cloned and expressed by Toole et al. (1984) and Wood et al. (1984). It
was one of the largest genes cloned to that time and, with the study of
Schwartz et al. (1990), became the largest cloned protein to be used in
clinical trials. Lewis et al. (1985) reported that a hemophiliac who
received a liver transplant from a normal donor had nearly normal levels
of factor VIII coagulant activity in the postoperative period.
Through a suppressive effect on premature termination codons,
aminoglycoside antibiotics such as gentamicin have been used for
therapeutic benefit in a number of conditions including cystic fibrosis
(602421) and Duchenne muscular dystrophy (300377). James et al. (2005)
evaluated the effect of gentamicin on the factor VIII and factor IX
levels of severe hemophiliacs with known nonsense mutations. They
concluded that gentamicin was unlikely to be an effective treatment for
severe hemophilia because of its potential toxicity and the minimal
response observed.
In hemophilic SCID mice, Aronovich et al. (2006) reported successful
treatment of hemophilia by transplantation of fetal pig spleen harvested
at embryonic day 42 before the appearance of mature T cells. The
transplanted tissue exhibited good growth and subsequent expression of
factor VIII, leading to complete alleviation of hemophilia within 2 to 3
months after transplant. The results provided proof of principle that
transplantation of fetal spleen can correct hemophilia while avoiding
graft versus host disease.
- Gene Therapy
Continuous delivery of factor VIII protein in hemophiliacs by gene
therapy would represent a major clinical advance. Conceptually,
retroviral vectors can permanently insert the FVIII gene into DNA of the
whole cell and, therefore, appear to be the most suitable vehicles for
gene therapy. However, most retroviral vector systems have shown poor
performance in the production of factor VIII from primary cells in vitro
and in vivo. Dwarki et al. (1995) used the highly efficient MFG
retroviral vector system to transfer FVIII cDNA into murine and human
cells (primary and established cell lines). The cDNA contained an open
reading frame of 2,351 amino acids and lacked the B domain, which is not
required for procoagulant activity in vitro or in vivo. In contrast to
previous reports, Dwarki et al. (1995) demonstrated high transduction
efficiency and a high rate of factor VIII production. They also
demonstrated that factor VIII-secreting cells transplanted into
immune-deficient mice gave rise to substantial levels of factor VIII in
the plasma.
VandenDriessche et al. (1999) demonstrated that hemophilia A could be
corrected by in vivo gene therapy using retroviral vectors. Newborn
FVIII-deficient mice were injected intravenously with retroviral vectors
expressing high levels of human FVIII. High levels of functional human
FVIII production could be detected in 6 of 13 animals, 4 of which
expressed physiologic or higher levels. Five of the 6 expressors
produced FVIII and survived an otherwise lethal tail clipping,
demonstrating phenotypic correction of the bleeding disorder. FVIII
expression was sustained for more than 14 months. Gene transfer occurred
into liver, spleen, and lungs, with predominant FVIII mRNA expression in
the liver. Six of the 7 animals with transient or no detectable human
FVIII developed FVIII inhibitors.
Kay and High (1999) discussed, in general terms, gene therapy for the
hemophilias. They pointed out that gene therapy for factor VIII
deficiency has been relatively more difficult than that for factor IX
deficiency because of the large size of the factor VIII coding region.
Roth et al. (2001) tested the safety of a nonviral somatic cell gene
therapy system in patients with severe hemophilia A. Skin fibroblasts
obtained by skin biopsy were transfected with a plasmid carrying
sequences of the factor VIII gene. Cells that produced factor VIII were
selected, cloned, and propagated in vitro. The cloned cells were then
harvested and administered to the patients by laparoscopic injection
into the omentum. Follow-up 12 months after implantation of the
genetically altered cells showed no serious adverse reactions. No
inhibitors of factor VIII were detected. In 4 of the 6 patients treated,
plasma levels of factor VIII activity rose above the levels observed
before the procedure. Coincident with the increase in factor VIII
activity was a decrease in bleeding, a reduction in the use of exogenous
factor VIII, or both. In the patient with the highest level of factor
VIII activity, the clinical changes lasted approximately 10 months.
Mannucci and Tuddenham (2001) reviewed the hemophilias. They stated that
hemophilia is likely to be the first common severe genetic condition to
be cured by gene therapy. Apart from the long-term consequences of viral
infections transmitted by infected blood products, there seem to be only
2 remaining problems: first, the development of high titers of
antibodies against factor VIII or factor IX, and second, the challenge
to society that four-fifths of all patients with hemophilia, mainly
those in developing countries, receive no treatment. They suggested that
less expensive replacement therapy, such as large-scale production and
purification of factor VIII and factor IX from the milk of transgenic
farmyard animals, might be a solution.
Pasi (2001) reviewed gene therapy for hemophilia.
POPULATION GENETICS
Hemophilia A is caused by a deficiency of factor VIII and it affects
between 1 in 5000 to 1 in 10,000 males in most populations.
Soucie et al. (1998) studied the frequency of hemophilia A and
hemophilia B in 6 U.S. states: Colorado, Georgia, Louisiana,
Massachusetts, New York, and Oklahoma. A hemophilia case was defined as
a person with physician-diagnosed hemophilia A or B and/or a measured
baseline factor VIII or IX activity (FA) of 30% or less. Case-finding
methods included patient reports from physicians, clinical laboratories,
hospitals, and hemophilia treatment centers. Once identified, trained
data abstractors collected clinical and outcome data retrospectively
from medical records. Among cases identified in 1993 to 1995, 2,743 were
residents of the 6 states in 1994, of whom 2,156 (79%) had hemophilia A.
Of those with factor VIII measurements, 1,140 (43%) had severe (FA less
than 1%), 684 (26%) had moderate (FA of 1-5%), and 848 (31%) had mild
(FA of 6-30%) disease. The age-adjusted prevalence of hemophilia in all
6 states in 1994 was 13.4 cases per 100,000 males (10.5 hemophilia A and
2.9 hemophilia B). The prevalence by race/ethnicity was 13.2 cases per
100,000 white, 11.0% among African American, and 11.5% among Hispanic
males. Application of age-specific prevalence rates from the 6
surveillance states to the U.S. population resulted in an estimated
national population of 13,320 cases of hemophilia A and 3,640 cases of
hemophilia B. For the 10-year period 1982 to 1991, the average incidence
of hemophilia A and B in the 6 surveillance states was estimated to be 1
in 5,032 live male births.
ANIMAL MODEL
Earlier it was assumed that the hemophilia gene was lethal in homozygous
females. That this was not the case was first demonstrated in the dog by
Brinkhous and Graham (1950) who studied homozygous hemophilic female
dogs. Splenic transplantation to dogs with hemophilia A corrects the
coagulation defect (Norman et al., 1968).
Lozier et al. (2002) studied the nature of the molecular defect in the
F8 gene in the Chapel Hill colony of factor VIII-deficient dogs started
by Brinkhous and Graham (1950). They found that the defect in these dogs
replicates the factor VIII gene inversion (306700.0067) commonly seen in
humans with severe hemophilia A.
Conventional gene therapy of hemophilia A relies on the transfer of
factor VIII cDNA. Chao et al. (2003) adopted a different approach to the
molecular treatment of hemophilia A in mice. They carried out
spliceosome-mediated RNA trans-splicing (SMaRT) to repair mutant factor
VIII mRNA. A pre-trans-splicing molecule (PTM) corrected endogenous
factor VIII mRNA in F8 knockout mice with the hemophilia A phenotype,
producing sufficient functional factor VIII to correct the hemophilia A
phenotype. The results indicated the feasibility of using SMaRT to
repair RNA for the treatment of genetic diseases. The use of mRNA repair
may circumvent the problems associated with conventional methods of
delivering full-length cDNA for gene therapy.
HISTORY
Early reports of hemophilia families emanated from this country
beginning with a newspaper account in 1792 (McKusick, 1962) and
continuing with medical reports by Otto in 1803 and Hay in 1813
(McKusick, 1962). Cone (1979) called attention to an amazingly clear
description of the genetics and rheumatic complications of hemophilia by
Dr. James N. Hughes of Simpsonville, Kentucky, in 1832.
Although the type of hemophilia, hemophilia A or hemophilia B, is not
known, the occurrence of hemophilia in the last Tsar of Russia and other
descendants of Queen Victoria through the maternal lines is well
documented (McKusick, 1965). Gill et al. (1994) reported DNA studies on
9 skeletons found in a shallow grave in Ekaterinburg, Russia, in July
1991 and tentatively identified by Russian forensic authorities as the
remains of the last Tsar, Tsarina, 3 of their 5 children, the Royal
Physician and 3 servants. DNA-based sex testing and short-tandem repeat
analysis confirmed that a family group was present in the grave.
Analysis of mitochondrial DNA revealed an exact sequence match between
the putative Tsarina and the 3 children and a living maternal relative.
Amplified mtDNA extracted from the remains of the putative Tsar
demonstrated heteroplasmy at a single base within the mtDNA control
region. One of these sequences matched 2 living maternal relatives of
the Tsar. The DNA data indicated that 1 of the princesses and Tsarevich
Alexei were missing from the grave.
A paternal age effect may have been operative in the case of the 'royal
hemophilia' in the descendants of Queen Victoria who was clearly a
carrier. There were no earlier cases in the family and Victoria's father
was 52 years old at the time of her birth (McKusick, 1965).
The identification of the remains of the Romanov family by DNA analysis
(Gill et al., 1994; Ivanov et al., 1996) and the laying to rest of the
Romanov bones 80 years to the day after their assassination (17 July
1998) prompted Stevens (1999) to review the history of hemophilia in the
royal families of Europe, with a pedigree chart. In the studies reported
by Gill et al. (1994) and Ivanov et al. (1996), 5 of the bodies were
clearly related, and 3 were those of female sibs. Furthermore, a sample
of maternally inherited mtDNA suspected of belonging to Tsarina
Alexandra matched a sample generously donated by her grandnephew, Philip
Duke of Edinburgh. Finding a reference sample for Nicholas proved more
difficult. Two distant relatives with the same matrilineage agreed to
help. The mtDNA sequences the Tsar's 2 relatives were identical to each
other, but where the relatives had a T at nucleotide 16169, the bone
mtDNA of Nicholas surprisingly had a C. Gill et al. (1994) concluded
that this represented heteroplasmy with 2 populations of mitochondria
within his cells that contained either a C or a T at this position. He
estimated, furthermore, the probability of the remains belonging to the
Tsar as being 98.5%. The Russian Orthodox Church demanded more evidence,
leading to the exhumation of the Grand Duke Georgij Romanov, who had
died before his brother of tuberculosis. Bone samples were studied at
the Armed Forces Institute of Pathology DNA Identification Laboratory in
Maryland. Analysis was carried out at the request of the Russian federal
government. Results showed that the mtDNA of both Grand Duke Georgij and
Tsar Nicholas had the same heteroplasmy. This was the first time that
heteroplasmy had been applied in human identification. Ivanov et al.
(1996) calculated a likelihood ratio for the authenticity of the remains
in excess of 100 million to 1, not including other anthropologic and
forensic evidence. The events of 17 July 1998 emphasized the gap between
church and science. The patriarch Alexksi II continued to insist that
DNA tests were fallible; the Archbishop of St. Petersburg did not attend
the burial service at the ancestral church of the Peter and Paul
Fortress in St. Petersburg. The remains of Tsarevich Alexis and one of
his sisters, possibly Maria, were not found. The most famous claimant to
the title of Anastasia was Anna Anderson, who died in 1984 in the United
States and was cremated, but 4 years previously had undergone emergency
surgery for an ovarian tumor. DNA fingerprinting by several groups on
the laparotomy material dismissed the posthumous claims of Anna Anderson
(Stoneking et al., 1995).
Stevens (1999) also reviewed hemophilia in the Spanish royal family and
the medical history of Victoria's hemophilic son, Leopold. His birth was
a landmark for other reasons. Dr. John Snow (who later identified the
water pump in Broad Street as the source of the London cholera outbreak)
administered chloroform to Victoria in childbirth with Leopold and
created a breakthrough in anesthesia. Leopold was a severe hemophiliac.
Queen Victoria was obviously ashamed of Leopold and spoke of him
disparagingly. Because of his incapacity and confinement to bed for
protracted periods, he read widely and was undoubtedly the most
intelligent and intellectual of Victoria's children. Leopold's letters
recounted his problems with the arthropathy of hemophilia. At the age of
24, Leopold became one of his mother's private secretaries and had
access to state papers. In 1881, Victoria created Leopold Duke of Albany
and the following year he married Princess Helena of Waldeck, sister of
the Dutch Queen. They had 2 children. Princess Alice was an obligate
carrier and had a hemophilic son (Rupert, Viscount Trematon) who died in
1928 at the age of 21. Charles Edward Leopold was born posthumously, as
his father had died at the age of 31 after a fall down a staircase in
Cannes causing intracranial hemorrhage. Victoria's father did not have
hemophilia but apparently did have porphyria, inherited from his father,
George III.
Mannucci and Tuddenham (2001) stated that none of the descendants of
Queen Victoria who were known to be affected were alive; the last one,
Waldemar, died in 1945. They stated, however, that Victoria's
great-great-granddaughter Olympia, from the Spanish branch, had a son,
Paul Alexander, who died in childhood of a 'blood' disorder, and she may
therefore be the last surviving carrier, testing of whom might determine
the nature of the type of hemophilia, A or B, and perhaps even the
precise mutation in the royal family.
Ratnoff and Lewis (1975) described a family with a bizarre X-linked
bleeding disorder that probably represents a variant of hemophilia A.
They called it Heckathorn disease after one of the affected persons.
In the description of substitutions causing hemophilia A and listed as
allelic variants, the number of the amino acid residue in the mature
factor VIII protein is used. The leader sequence of the proprotein has
an additional 19 amino acids. The mature factor VIII protein has 2,332
amino acids. (The gene is 186 kb long, with 26 exons.)
Wacey et al. (1996) described HAMSTeRS (the hemophilia A mutation search
test and resource site), the homepage of the factor VIII mutation
database maintained in the unit of EDG Tuddenham at Royal Postgraduate
Medical School in London. The authors discussed how to access the
database via the Internet. Kemball-Cook and Tuddenham (1997) gave
further information on the HAMSTeRS database which had been completely
updated with easy submission for point mutations, deletions, and
insertions via e-mail of custom-designed forms. A methods section
devoted to mutation detection had been added, highlighting issues such
as choice of technique and PCR primer sequences.
Allelic Variants:
.0001
HEMOPHILIA A
F8, ARG2307TER
Gitschier et al. (1985) identified this mutation due to a CGA-to-TGA
change in codon 2326 in exon 26 in a patient with severe hemophilia A.
Nonsense mutations and a different missense (arg-to-gln) mutation have
previously been observed in the same codon. It was pointed out that the
G-to-T transversion is contrary to the rule of CG-to-TG mutations at CG
dinucleotides, which represent the overwhelming majority.
.0002
HEMOPHILIA A
F8, ARG2209TER
In a severe case of hemophilia A, Gitschier et al. (1985) found change
in codon 2228 in exon 24 from CGA to TGA to result in conversion of
arg2209 to stop. This mutation has also been found by others
(Youssoufian et al., 1986).
.0003
HEMOPHILIA A
F8, EX26DEL
In a patient with severe hemophilia A, Gitschier et al. (1985) found
deletion of about 22 kb including exon 26.
.0004
HEMOPHILIA A
F8, ARG2116TER
In a case of severe hemophilia A (JH5), Youssoufian et al. (1986) found
change of codon 2135 from CGA to TGA, resulting in conversion of amino
acid 2116 to stop.
.0005
HEMOPHILIA A
F8, EX6DEL
In a case of severe hemophilia A (JH6), Youssoufian et al. (1987) found
deletion of exon 6.
In a patient with severe hemophilia A (patient 2213), Levinson et al.
(1990) found a deletion of exon 6 of the factor VIII gene. Schwaab et
al. (1993) identified 2 patients with this deletion. See also Lin et al.
(1993) and Antonarakis et al. (1995).
.0006
HEMOPHILIA A
F8, EX14DEL
In a case of severe hemophilia A (JH7), Youssoufian et al. (1987) found
deletion of exon 14.
In 3 patients with severe hemophilia A, Krepelova et al. (1992) found a
deletion of exon 14 of the factor VIII gene. See also 306700.0029,
306700.0047, and 306700.0049.
.0007
HEMOPHILIA A
F8, EX24-25DEL
In a case of severe hemophilia A (JH8), Youssoufian et al. (1987) found
deletion of exons 24 and 25.
.0008
HEMOPHILIA A
F8, EX23-25DEL
In a case of severe hemophilia A (JH9), Youssoufian et al. (1987) found
deletion of exons 23-25.
.0009
HEMOPHILIA A
F8, EX22DEL
In a case of moderately severe hemophilia A (JH10), Youssoufian et al.
(1987) found 'in-frame' deletion of exon 22.
.0010
HEMOPHILIA A
F8, EX26DEL
In a case of severe hemophilia A (JH12), Antonarakis et al. (1995) found
deletion of exon 26. The mother showed mosaicism for this mutation.
.0011
HEMOPHILIA A
F8, EX1DEL
In a case of severe hemophilia A (JH13), Youssoufian et al. (1988) found
deletion of exon 1.
In a patient with severe hemophilia A (patient H309), Millar et al.
(1990) found a deletion of exon 1 of the factor VIII gene. See also
Wehnert et al. (1989), Higuchi et al. (1991), Schwaab et al. (1993), and
Antonarakis et al. (1995), who reported patients with deletion of exon
1.
.0012
HEMOPHILIA A
F8, ARG2147TER
In a case of severe hemophilia A (JH14), Youssoufian et al. (1988) found
a CGA to TGA change in codon 2166, resulting in a change in ARG2147 to a
termination codon.
.0013
HEMOPHILIA A
F8, NEW SPLICE DONOR, IVS4
In a case of mild hemophilia A (JH17), Youssoufian et al. (1988) found
the creation of a new splice donor site created in intron 4 by a GAA to
AAA change.
.0014
HEMOPHILIA A
F8, ARG2209GLN
In 2 cases of severe hemophilia A (JH18, JH19), Youssoufian et al.
(1988) found a CGA-to-CAA change in codon 2228, resulting in
substitution of glutamine for arginine as amino acid 2209. This mutation
has also been found by others (Bernardi et al., 1989; Levinson et al.,
1990; Traystman et al., 1990).
.0015
HEMOPHILIA A
F8, GLU272GLY
Youssoufian et al. (1988) demonstrated the usefulness of DNA
amplification followed by direct nucleotide sequencing in the search for
mutations in X-linked disorders because of the unambiguous sequencing
data obtained when the amplified DNA is from a male patient. In a
17-year-old Greek male with moderately severe hemophilia A (JH20), they
detected a mutation by analysis of genomic DNA with TaqI; contrary to
previous experience, the mutation was not a C-to-T or G-to-A transition.
(The unifying mechanism of these mutations is thought to be
methylation-induced C-to-T transitions at CpG dinucleotides involving
either the coding or the complementary strand of DNA; see Bird (1980).)
In this case the point mutation was in exon 7, where codon 291 for
glutamate (GAA) was changed to one for glycine (GGA), leading to a
change in amino acid 272 of the mature factor VIII protein. The mutation
had arisen de novo in a germ cell of the patient's mother. The patient
had 2% factor VIII activity, 3.5% factor VIII antigen, and moderate
hemophilia A.
.0016
HEMOPHILIA A
F8, EX2-3DEL
In a case of severe hemophilia A (JH21), Youssoufian et al. (1988) found
deletion of exons 2 and 3.
In a patient with severe hemophilia A (patient 656), Higuchi et al.
(1988) found a deletion of exons 2-3 of the factor VIII gene.
.0017
HEMOPHILIA A
F8, EX3-13DEL
In a case of severe hemophilia A (JH22), Youssoufian et al. (1988) found
deletion of exons 3-13.
.0018
HEMOPHILIA A
F8, EX4-25DEL
In a case of severe hemophilia A (JH23), Youssoufian et al. (1988) found
deletion of exons 4-25.
.0019
HEMOPHILIA A
F8, EX7-14DEL
In a case of severe hemophilia A (JH24), Youssoufian et al. (1988)found
deletion of exons 7-14.
.0020
FACTOR VIII POLYMORPHISM
F8, LINE INS, IVS10
In a normal individual (JH25), Woods-Samuels et al. (1989) found
insertion of 0.7 kb of LINE sequence in intron 10.
.0021
HEMOPHILIA A
F8, EX26DEL
In a patient with severe hemophilia A (JH26), Youssoufian et al. (1988)
found deletion of exon 26. Also see Gitschier et al. (1985), who found
this deletion in a British patient, and Bernardi et al. (1989).
.0022
HEMOPHILIA A
F8, LINE INS, EX14
In 2 brothers with severe hemophilia A (JH27, JH28), Kazazian et al.
(1988) found insertion of 3.8 kb of LINE sequence in exon 14.
.0023
HEMOPHILIA A
F8, EX15DEL
In a patient (JH29) with severe hemophilia A and a translocation
t(X;17), Antonarakis et al. (1995) found deletion of exon 15.
.0024
HEMOPHILIA A
F8, 2-BP DEL, EX8
In a patient with severe hemophilia A (JH31), Higuchi et al. (1990)
found deletion of GA from codon 360 GAA in exon 8.
.0025
HEMOPHILIA A
F8, ARG2307LEU
In a Japanese patient with mild hemophilia A (JH32), Inaba et al. (1989)
found a CGA-to-CTA change in codon 2326 in exon 26, resulting in
substitution of leucine for arginine at amino acid 2307. PCR and
nucleotide sequencing were used to identify the defect, which caused an
alteration in a TaqI site.
.0026
HEMOPHILIA A
F8, ARG1941GLN
In a Japanese patient with mild hemophilia A (JH33), Antonarakis
(unpublished observations) found a CGA-to-CAA change in exon 1960 in
exon 18, resulting in substitution of glutamine for arginine as amino
acid 1941. This mutation was also found in a Finnish patient by Levinson
et al. (1990).
.0027
FACTOR VIII (OKAYAMA)
F8, ARG372HIS
In a case of CRM-positive hemophilia A (JH35), Arai et al. (1989) found
a change of arginine-372 to histidine, resulting from a CGC-to-CAC
change in codon 391 in exon 8. The mutation was at the site of thrombin
cleavage. Shima et al. (1989) found the same change in what they called
factor VIII (Okayama).
.0028
HEMOPHILIA A
F8, GLU1686TER
In a patient with severe hemophilia A (JH36), Higuchi et al. (1990)
found a CAG-to-TAG change in codon 1705, causing replacement of glutamic
acid 1686 by a stop signal.
.0029
HEMOPHILIA A
F8, EX14DEL
In a patient with severe hemophilia A (JH37), Higuchi et al. (1989)
found deletion of exon 14.
.0030
HEMOPHILIA A
FACTOR VIII (EAST HARTFORD)
F8, ARG1689CYS
In a patient with moderately severe hemophilia A of a CRM-positive type,
Gitschier (1988) found a CGC-to-TGC change in codon 1708 in exon 14,
resulting in a change of arginine-1689 to cysteine. The mutation affects
the thrombin cleavage site. The same mutation was subsequently found in
additional patients (JH38, JH39) by Arai et al. (1990). Aly et al.
(1992) found that cysteamine, which is known to modify mutant proteins
with an arg-to-cys substitution, enhances the procoagulant activity of
the mutant factor VIII, which they referred to as factor VIII-East
Hartford. Aly and Hoyer (1992) demonstrated that the East Hartford
mutant protein had procoagulant activity when separated from von
Willebrand factor; this was taken to indicate that the dissociation of
factor VIII from VWF is an essential effect of factor VIII light chain
cleavage at arginine-1689.
.0031
HEMOPHILIA A
F8, TYR1680PHE
In a patient with mild hemophilia A (JH40), Higuchi et al. (1990) found
a TAT-to-TTT change in codon 1699, resulting in substitution of
phenylalanine for tyrosine at amino acid 1680. The mutation affected the
von Willebrand binding site.
.0032
HEMOPHILIA A
F8, TYR1709CYS
In a patient with hemophilia A (JH41), Traystman et al. (1990) found a
TAT-to-TGT change in codon 1728 of exon 14, leading to substitution of
cysteine for tyrosine-1709.
.0033
HEMOPHILIA A
F8, EX11-18DEL
In a case of severe hemophilia A (JH1), Antonarakis et al. (1985) found
deletion of exons 11-18.
.0034
HEMOPHILIA A
F8, ARG1941TER
In a case of severe hemophilia A (JH2), Antonarakis et al. (1985) found
change in codon 1960 in exon 18 from CGA to TGA which converted arg1941
to stop. Youssoufian et al. (1986) found the same mutation in another
case of severe hemophilia A (JH3).
.0035
HEMOPHILIA A
F8, EX3DEL
In a patient with severe hemophilia A, Higuchi et al. (1989) found a
deletion of exon 3 about 2 kb in length.
.0036
FACTOR VIII POLYMORPHISM
F8, 7-KB DEL, IVS1
Levinson et al. (1990) found a deletion of 7 kb from IVS1 as a presumed
normal variant of factor VIII.
.0037
HEMOPHILIA A
F8, EX1-5DEL
In a patient with severe hemophilia A, Higuchi et al. (1989) found a 35+
kb deletion removing exons 1 to 5.
.0038
HEMOPHILIA A
F8, EX1-22DEL
In a patient with severe hemophilia A, Lillicrap et al. (1986) found a
127+ kb deletion that removed exons 1 to 22.
.0039
HEMOPHILIA A
F8, EX26DEL
In a patient with severe hemophilia A, Higuchi et al. (1989) found
deletion of exon 26.
In a patient with severe hemophilia A (patient HDX5), Bernardi et al.
(1989) found a deletion of exon 26 of the factor VIII gene. This
deletion was also reported by Nafa et al. (1990), Lavergne et al.
(1992), Schwaab et al. (1993), and Antonarakis et al. (1995).
.0040
HEMOPHILIA A
F8, EX1-26DEL
In a patient with severe hemophilia A, Casarino et al. (1986) found a
178+ kb deletion that removed exons 1 to 26.
In a patient with severe hemophilia A (patient H1) and factor VIII
inhibitors, Casula et al. (1990) found a total deletion of the factor
VIII gene.
.0041
HEMOPHILIA A
F8, ARG372CYS
This change was found in a case of moderately severe hemophilia A by
Shima et al. (1989). The mutation is in the thrombin cleavage activator
site. O'Brien et al. (1990) studied the relationship between structure
and dysfunction.
.0042
HEMOPHILIA A
F8, ARG2307GLN
Gitschier et al. (1986) found this substitution in a case of mild
hemophilia A.
.0043
HEMOPHILIA A
F8, LEU2166SER
Levinson et al. (1990) found this substitution in a patient with less
than 1% factor VIII activity and clinically severe hemophilia. The
substitution was caused by a T-to-C transition at position 6555 in exon
23.
.0044
HEMOPHILIA A
F8, ARG2116PRO
Levinson et al. (1987) found this substitution in a severe case of
hemophilia A.
.0045
HEMOPHILIA A
F8, SER170LEU
Chan et al. (1989) found this substitution in a moderately severe case
of hemophilia A.
.0046
HEMOPHILIA A
F8, EX15-18DEL
In a patient with severe hemophilia A, Bardoni et al. (1988) found
deletion of exons 15 to 18.
.0047
HEMOPHILIA A
F8, EX14DEL
In a patient with severe hemophilia A with inhibitors, Higuchi et al.
(1989) found deletion of exon 14.
.0048
HEMOPHILIA A
F8, EX23-25DEL
In a patient with severe hemophilia A, Gitschier et al. (1985) and
Gitschier (1988) found deletion of exons 23 to 25 as a result of a
complex rearrangement with deletion-duplication.
.0049
HEMOPHILIA A
F8, EX14DEL
In a patient with severe hemophilia A accompanied by inhibitors, Mikami
(1988) found deletion of exon 14.
.0050
HEMOPHILIA A
F8, EX7-9DEL
In a patient with severe hemophilia A with inhibitors, Higuchi et al.
(1989) found deletion of exons 7 to 9.
.0051
HEMOPHILIA A
F8, EX5DEL
In a patient with severe hemophilia A, Levinson et al. (1990) found a 3-
to 6-kb deletion removing exon 5.
.0052
HEMOPHILIA A
F8, EX5DEL
In a patient with severe hemophilia A, Levinson et al. (1990) found a
deletion of about 10 kb removing exon 5.
.0053
HEMOPHILIA A
F8, EX5DEL
In a patient with severe hemophilia A, Briet et al. (1989) found a
deletion of about 2 kb removing exon 5. Somatic and gonadal mosaicism
was demonstrated in the mother.
.0054
HEMOPHILIA A
F8, EX5-6 DEL
In a patient with severe hemophilia A with inhibitors, Levinson et al.
(1990) found a deletion of 3-10 kb removing exons 5 and 6.
.0055
HEMOPHILIA A
F8, ARG336TER
Gitschier et al. (1986) found this substitution in a patient with severe
hemophilia A.
.0057
HEMOPHILIA A
F8, ASN1922ASP
Traystman et al. (1990) demonstrated this mutation in patients with
hemophilia A.
.0058
HEMOPHILIA A
F8, CYS329ARG
In a patient with severe hemophilia A, Kogan and Gitschier (1990)
demonstrated a thymine-to-cytosine mutation that changed the cysteine at
codon 329 to an arginine. They used denaturing gel electrophoresis for
this purpose.
.0059
HEMOPHILIA A
F8, VAL326LEU
In a patient with severe hemophilia A, Kogan and Gitschier (1990)
demonstrated a guanine-to-cytosine change within codon 326 resulting in
a valine-to-leucine change.
Higuchi et al. (1990) found the same mutation in a patient with severe
hemophilia A (JH30).
.0060
HEMOPHILIA A
F8, 4-BP DEL, FS
By means of denaturing gradient gel electrophoresis, Kogan and Gitschier
(1990) demonstrated a deletion of 4 nucleotides within the region coding
for the first acidic domain. The mutation caused a frameshift and a
truncated protein product. The deletion occurred in a repetitive AAT and
AAG motif. Small deletions in repeat sequences are thought to occur by a
'slipped mispairing' mechanism during DNA replication.
.0061
HEMOPHILIA A
F8, EX13DUP
In a patient with mild hemophilia A, Murru et al. (1990) characterized a
duplication in exon 13. The duplication was the result of nonhomologous
breakage and reunion of 2 misaligned wildtype chromosomes. Sequence
analysis of the breakpoint region showed AT-rich sequences and possible
topoisomerase I sites, whose involvement in cases of illegitimate
recombination has been postulated.
.0062
HEMOPHILIA A
F8, ARG427TER
Berg et al. (1990) took advantage of the fact that extremely low
background levels of correctly spliced mRNA transcripts of
tissue-specific genes can be demonstrated in a number of supposedly
nonexpressing' cell types. This 'ectopic' or 'illegitimate'
transcription was used to demonstrate the diagnostic utility of such
transcripts in the construction of specific cDNAs derived from readily
accessible 'nonexpressing' tissue, e.g., lymphocytes in the case of
hemophilia A. Using PCR and direct sequencing, they demonstrated a novel
mutation: a CGA-to-TGA transition at arginine 427.
.0063
HEMOPHILIA A
F8, GLU1704LYS
In a patient with sporadic severe hemophilia A, Paynton et al. (1991)
identified a G-to-A transition resulting in substitution of lysine for
glutamate-1704 (E1704K). The origin of the mutation was shown to be in
the maternal grandfather who was 27 years old when his daughter was
conceived.
.0064
HEMOPHILIA A
F8, PRO2300SER
In a sporadic case of mild hemophilia A, Paynton et al. (1991)
demonstrated a C-to-T transition that resulted in substitution of serine
for proline-2300. Paynton et al. (1991) used PCR amplification of
specific alleles (PASA) to screen 96 unrelated hemophiliacs for the
P2300S mutation; none of these patients had the mutation.
.0065
HEMOPHILIA A
F8, MET1772THR
In a study of the molecular defects responsible for crossreacting
material-positive hemophilia A, Aly et al. (1992) found 2 patients in
whom the nonfunctional factor VIII-like protein had abnormal,
slower-moving heavy or light chains on SDS/PAGE. Both patients had
severe hemophilia A with less than 1% of normal factor VIII activity but
with normal plasma level of factor VIII antigen. By denaturing gradient
gel electrophoresis screening of PCR-amplified products of the factor
VIII coding DNA sequence, followed by nucleotide sequencing of the
abnormal PCR products, they identified in 1 patient a met1772-to-thr
mutation that created a potential new N-glycosylation site at
asparagine-1770 in the factor VIII light chain. In the second patient,
an isoleucine-to-threonine substitution at position 566 created a
potential new N-glycosylation site at asparagine-564 in the A2 domain of
the factor VIII heavy chain.
Abnormal N-glycosylation, blocking factor VIII probe procoagulant
activity, represented a previously unrecognized mechanism for the
pathogenesis of severe hemophilia A.
.0066
HEMOPHILIA A
F8, ILE566THR
See 306700.0065.
.0067
HEMOPHILIA A, SEVERE
F8, IVS22 INV
Lakich et al. (1993) concluded that many mutations in the F8C gene
result from recombination between homologous sequences within intron 22
of the F8C gene and those upstream of the gene. Such a recombination
would lead to an inversion of all intervening DNA and a disruption of
the gene. Among 23 patients with severe hemophilia A, Naylor et al.
(1993) found that approximately 40% were on the basis of this mutation
involving intron 22.
It is hypothesized that the inversion mutations occur almost exclusively
in germ cells during meiotic cell division by an intrachromosomal
recombination between a 9.6-kb sequence within intron 22 and 1 of 2
almost identical copies located about 300 kb distal to the factor VIII
gene at the telomeric end of the X chromosome. Most inversion mutations
originate in male germ cells, where the lack of bivalent formation may
facilitate flipping of the telomeric end of the single X chromosome.
Oldenburg et al. (2000) reported the first instance of intron 22
inversion presenting as somatic mosaicism in a female, affecting only
about 50% of lymphocyte and fibroblast cells of the proposita. Supposing
a postzygotic de novo mutation as the usual cause of somatic mosaicism,
the finding implies that the intron 22 inversion mutation is not
restricted to meiotic cell divisions but can also occur during mitotic
cell divisions, either in germ cell precursors or in somatic cells.
Lozier et al. (2002) found that the defect in the Chapel Hill hemophilia
A dog colony started by Brinkhous and Graham (1950) replicates the F8
gene inversion commonly seen in humans with severe hemophilia A.
.0068
HEMOPHILIA A
F8, IVS6DS, A-G, +3, 186-BP DEL, EX5-6 DEL
Bidichandani et al. (1994) studied 15 randomly selected hemophilia A
patients, 9 of whom were severely affected. They reported a new mutation
affecting the intron 6 splice donor site in the factor VIII gene of 2
patients, that corresponds to an exon skipping event involving exon 5
and 6. The mutation is an A-to-G substitution at position +3 in the
splice donor site of intron 6 in both the patients. This exon skipping
event left the translational frame intact, and the resultant in-frame
deletion of 186-bp in the mature mRNA is predicted to cause a shortening
of the mature factor VIII polypeptide by 62 amino acid residues. Direct
sequencing showed that exon 5 is consistently skipped along with exon 6
in the mature factor VIII mRNA. Both patients have a disease of moderate
severity and residual factor VIII activity 3% of the normal.
Bidichandani et al. (1994) noted that a patient lacking exon 5 and 6 in
the mature factor VIII mRNA due to gross DNA deletion has previously
been reported to have severe hemophilia A.
.0069
HEMOPHILIA A
F8, ARG-5TER
In 2 patients with hemophilia A, Pattinson et al. (1990) identified the
substitution of CGA to TGA at codon -5 in exon 1, resulting in a stop
codon. The C-to-T transition follows the rule of CG-to-TG mutations at
CG dinucleotides. This mutation has also been found by others (Reiner
and Thompson, 1992).
.0070
HEMOPHILIA A
F8, LEU7ARG
Antonarakis et al. (1995) reported this substitution in a patient with
less than 1% factor VIII activity and severe hemophilia A. The
substitution is caused by a CTG-to-CGG transversion at codon 7 in exon 1
of the A1 domain, resulting in arginine for leucine-7.
.0071
HEMOPHILIA A
F8, GLU11VAL
Diamond et al. (1992) found this substitution in a patient with mild
hemophilia A. The substitution is caused by a GAA-to-GTA transversion at
codon 11 in exon 1, resulting in valine for glutamic acid-11. This
mutation is found in the A1 domain.
.0072
HEMOPHILIA A
F8, 89-BP DEL, FS
Antonarakis et al. (1995) reported in a patient with severe hemophilia A
the deletion of 89 nucleotides from codon 14 to 29 in exon 1, resulting
in a frameshift.
.0073
HEMOPHILIA A
F8, GLY22CYS
Antonarakis et al. (1995) reported this substitution in 2 patients with
less than 1% factor VIII activity and severe hemophilia A. The
substitution is caused by a GGT-to-TGT transversion at codon 22 in exon
1 of the A1 domain, resulting in cysteine for glycine-22.
.0074
HEMOPHILIA A
F8, 10-BP INS, FS
In a patient with severe hemophilia A, Lin et al. (1993) identified the
insertion of 10 nucleotides (TTCCATTCAA) resulting in a frameshift
downstream from codon 38 in exon 2.
.0075
HEMOPHILIA A
F8, 2-BP DEL, FS
In a patient with severe hemophilia A, Lin et al. (1993) identified the
deletion of 2 nucleotides (AA) resulting in a frameshift downstream from
codon 48 in exon 2.
.0076
HEMOPHILIA A
F8, 4-BP DEL, FS
Antonarakis et al. (1995) reported in a patient with severe hemophilia A
the deletion of 4 nucleotides (GTTT) resulting in a frameshift
downstream from codon 50 in exon 2.
.0077
HEMOPHILIA A
F8, 2-BP DEL, FS
In a patient with severe hemophilia A, Antonarakis et al. (1995)
reported the deletion of 2 nucleotides (GT) resulting in a frameshift
downstream from codon 102 or 3 in exon 3.
.0078
HEMOPHILIA A
F8, 23-BP DEL, FS
Higuchi et al. (1991) identified in a patient with severe hemophilia A
the deletion of 23 nucleotides resulting in a frameshift downstream from
codon 104 in exon 3.
.0079
HEMOPHILIA A
F8, IVS4AS, A-G, -2
Antonarakis et al. (1995) reported the substitution of A to G at the
second nucleotide of the acceptor splice site of intron 4, resulting in
abnormal splicing. The patient had 1.7% factor VIII activity, 1.3%
factor VIII antigen, and a severe hemophilia A.
.0080
HEMOPHILIA A
F8, GLY70ASP
Antonarakis et al. (1995) reported this gly70-to-asp substitution in a
patient with less than 1% factor VIII activity and severe hemophilia A.
The substitution is caused by a GGT-to-GAT transition at codon 70 in
exon 3 of the A1 domain.
.0081
HEMOPHILIA A
F8, GLY73VAL
Diamond et al. (1992) found this substitution in a patient with mild
hemophilia A. The substitution is caused by a GGT-to-GTT transversion at
codon 73 in exon 3 of the A1 domain, resulting in valine for glycine-73.
.0082
HEMOPHILIA A
F8, VAL80ASP
Antonarakis et al. (1995) reported this val80-to-asp substitution in a
patient with less than 1% factor VIII activity and severe hemophilia A.
The substitution is caused by a GTT-to-GAT transversion at codon 80 in
exon 3 of the A1 domain.
.0083
HEMOPHILIA A
F8, VAL85ASP
Diamond et al. (1992) found this val85-to-asp substitution in a patient
with mild hemophilia A. The substitution is caused by a GTC-to-GAC
transversion at codon 85 in exon 3 of the A1 domain.
.0084
HEMOPHILIA A
F8, LYS89THR
Higuchi et al. (1991) found this lys89-to-thr substitution in a patient
with mild hemophilia A. The substitution is caused by an AAG-to-ACG
transversion at codon 89 in exon 3 of the A1 domain.
.0085
HEMOPHILIA A
F8, MET91VAL
Higuchi et al. (1991) found this substitution in a patient with moderate
hemophilia A. The substitution is caused by a ATG-to-GTG transition at
codon 91 in exon 3 of the A1 domain, resulting in valine for
methionine-91.
.0086
HEMOPHILIA A
F8, LEU98ARG
Antonarakis et al. (1995) reported this substitution in a patient with
less than 1% factor VIII activity and severe hemophilia A. It is caused
by a CTT-to-CGT transversion at codon 98 in exon 3 of the A1 domain,
resulting in arginine for leucine-98.
.0087
HEMOPHILIA A
F8, GLY111ARG
Lin et al. (1993) found this substitution in a patient with less than 1%
factor VIII activity and severe hemophilia A. The substitution is caused
by a GGA-to-CGA transversion at codon 111 in exon 3 of the A1 domain,
resulting in arginine for glycine-111.
.0088
HEMOPHILIA A
F8, GLU113ASP
Antonarakis et al. (1995) reported this glu113-to-asp substitution in a
patient with less than 1% factor VIII activity, severe hemophilia A and
inhibitors. It is caused by a GAA-to-GAC transversion at codon 113 in
exon 4 of the A1 domain of factor VIII.
.0089
HEMOPHILIA A
F8, TYR114CYS
Antonarakis et al. (1995) reported this tyr114-to-cys substitution in a
patient with 6.3% factor VIII activity, 10.7% factor VIII antigen, and
mild hemophilia A. The substitution is caused by a TAT-to-TGT transition
at codon 114 in exon 4. This mutation is found in the A1 domain of
factor VIII.
.0090
HEMOPHILIA A
F8, ASP116GLY
Antonarakis et al. (1995) reported this substitution in a patient with
less than 1% factor VIII activity and severe hemophilia A. The
substitution is caused by a GAT-to-GGT transition at codon 116 in exon 4
of the A1 domain, resulting in glycine for aspartic acid-116.
.0091
HEMOPHILIA A
F8, TYR118ILE
Antonarakis et al. (1995) reported this substitution in a patient with
2% factor VIII activity, 10.7% factor VIII antigen, and moderate
hemophilia A. The substitution is caused by a ACC-to-ATC transition at
codon 118 in exon 4 of the A1 domain, resulting in isoleucine for
tyrosine-118.
.0092
HEMOPHILIA A
F8, GLY145VAL
Diamond et al. (1992) found this gly145-to-val substitution in a patient
with mild hemophilia A. The substitution is caused by a GGT-to-GTT
transversion at codon 145 in exon 4 of the A1 domain.
.0093
HEMOPHILIA A
F8, PRO146SER
Lin et al. (1993) found a pro146-tp-ser substitution in a patient with
less than 1% factor VIII activity and severe hemophilia A. The
substitution is caused by a CCA-to-TCA transition at codon 146 in exon 4
of the A1 domain.
.0094
HEMOPHILIA A
F8, VAL162MET
Diamond et al. (1992) found this substitution in 5 patients with
3.5-8.5% factor VIII activity, 6-35.9% factor VIII antigen, and moderate
to mild hemophilia A. A GTG-to-ATG transition at codon 162 in exon 4 of
the A1 domain resulted in a val162-to-met change.
.0095
HEMOPHILIA A
F8, LYS166THR
Higuchi et al. (1991) found this lys166-to-thr substitution in a patient
with 19% factor VIII activity and mild hemophilia A. The substitution is
caused by an AAA-to-ACA transversion at codon 166 in exon 4 of the A1
domain.
.0096
HEMOPHILIA A
F8, ASP203VAL
Antonarakis et al. (1995) reported this substitution in a patient with
2% factor VIII activity, 8.5% factor VIII antigen, and moderate
hemophilia A. The substitution is caused by a GAT-to-GTT transversion at
codon 203 in exon 5 of the A1 domain and resulted in valine for aspartic
acid-203.
.0097
HEMOPHILIA A
F8, GLY205TRP
Higuchi et al. (1991) found this substitution in a patient with 3.2%
factor VIII activity and moderate hemophilia A. The substitution is
caused by a GGG-to-TGG transversion at codon 205 in exon 5 of the A1
domain, resulting in tryptophan for glycine-205.
.0098
HEMOPHILIA A
F8, 2-BP DEL, FS
In a patient with severe hemophilia A, Lin et al. (1993) identified the
deletion of 2 nucleotides (AG) resulting in a frameshift downstream from
codon 210-211 in exon 6.
.0099
HEMOPHILIA A
F8, IVS5AS, A-G, -2
In a patient with less than 1% factor VIII activity and severe
hemophilia A, Naylor et al. (1991) identified an A-to-G transition at
the second nucleotide of the acceptor splice site of intron 5, which
resulted in abnormal splicing.
.0100
HEMOPHILIA A
F8, IVS6DS, A-G, +3
In a patient with 3-4% factor VIII activity and moderate hemophilia A,
Bidichandani et al. (1994) identified the substitution of A to G at the
third nucleotide of the donor splice site of intron 6, which resulted in
abnormal splicing.
.0101
HEMOPHILIA A
F8, IVS6AS, G-C, -1
Antonarakis et al. (1995) reported that Antonarakis Kazazian identified
in a patient with less than 1% factor VIII activity and severe
hemophilia A a G-to-C transversion. The mutation is in the first
nucleotide of the acceptor splice site of intron 6 and resulted in
abnormal splicing.
.0102
HEMOPHILIA A
F8, GLY247GLN
Antonarakis et al. (1995) reported this substitution in a patient with
less than 1% factor VIII activity and severe hemophilia A. The
substitution is caused by a GGA-to-GAA transition at codon 247 in exon 7
of the A1 domain, resulting in glutamine for glycine-247.
.0103
HEMOPHILIA A
F8, TRP255TER
In a patient with hemophilia A, Antonarakis et al. (1995) reported the
substitution of TGG-to-TGA at codon 255 in exon 7, resulting in a stop
codon.
.0104
HEMOPHILIA A
F8, GLY259ARG
Antonarakis et al. (1995) reported this substitution in a patient with
less than 1% factor VIII activity and severe hemophilia A. The
substitution is caused by a GGA-to-AGA transition at codon 259 in exon 7
of the A1 domain, resulting in arginine for glycine-259.
.0105
HEMOPHILIA A
F8, 1-BP DEL, FS
In a patient with severe hemophilia A, Antonarakis et al. (1995)
reported the deletion of 1 nucleotide (T) resulting in a frameshift
downstream from codon 264 in exon 7.
.0106
HEMOPHILIA A
F8, VAL266GLY
Higuchi et al. (1991) found this substitution in a patient with mild
hemophilia A. The substitution is caused by a GTG-to-GGG transversion at
codon 266 in exon 7 of the A1 domain, resulting in glycine for
valine-266.
.0107
HEMOPHILIA A
F8, THR275ILE
Antonarakis et al. (1995) reported this substitution in a patient with
4-4.8% factor VIII activity, 20-40% factor VIII antigen, and moderate
hemophilia A. The substitution is caused by a ACA-to-ATA transition at
codon 275 in exon 7 of the A1 domain, resulting in isoleucine for
threonine-275.
.0108
HEMOPHILIA A
F8, ASN280ILE
Pieneman et al. (1993) found this substitution in a patient with 8-12%
factor VIII activity and mild hemophilia A. The substitution is caused
by a AAC-to-ATC transversion at codon 280 in exon 7 of the A1 domain,
resulting in isoleucine for asparagine-280.
.0109
HEMOPHILIA A
F8, ARG282HIS
Higuchi et al. (1991) found this substitution in a patient with less
than 1% factor VIII activity, 18% factor VIII antigen, and severe
hemophilia A. A CGC-to-CAC transition at codon 282 in exon 7 of the A1
domain results in an arg282-to-his change. The G-to-A transition follows
the rule of CG-to-CA mutations at CG dinucleotides. This mutation has
also been found by others (McGinniss et al., 1993; Naylor et al., 1993).
.0110
HEMOPHILIA A
F8, ARG282LEU
Antonarakis et al. (1995) reported this substitution in 2 patients with
less than 1% factor VIII activity and severe hemophilia A. It is caused
by a CGC-to-CTC transversion at codon 282 in exon 7 of the A1 domain,
resulting in leucine for arginine-282.
.0111
HEMOPHILIA A
F8, 1-BP DEL, FS
In a patient with severe hemophilia A, Antonarakis et al. (1995)
reported the deletion of 1 nucleotide (G), resulting in a frameshift
downstream from codon 283 in exon 7.
.0112
HEMOPHILIA A
F8, SER289LEU
McGinniss et al. (1993) found this substitution in a patient with 37%
factor VIII activity, 106% factor VIII antigen and mild hemophilia A.
The substitution is caused by a TCG-to-TTG transition at codon 289 in
exon 7 of the A1 domain, resulting in leucine for serine-289. The C-to-T
transition follows the rule of CG-to-TG mutations at CG dinucleotides.
.0113
HEMOPHILIA A
F8, PHE293SER
Higuchi et al. (1991) found this substitution in 3 patients with 7-21.5%
factor VIII activity, 2-17.9% factor VIII antigen, and mild hemophilia
A. An ACT-to-GCT transition at codon 295 in exon 7 of the A1 domain
results in alanine for threonine-295.
.0114
HEMOPHILIA A
F8, THR295ALA
Higuchi et al. (1991) found this substitution in 3 patients with 7-21.5%
factor VIII activity, 2-17.9% factor VIII antigen, and mild hemophilia
A. The substitution is caused by a ACT-to-GCT transition at codon 295 in
exon 7 of the A1 domain, resulting in alanine for threonine-295.
.0115
HEMOPHILIA A
F8, 1-BP DEL, FS
(Antonarakis et al. (1995)) reported in a patient with severe hemophilia
A the deletion of 1 nucleotide (G), resulting in a frameshift downstream
from codon 296 in exon 7.
.0116
HEMOPHILIA A
F8, LEU308PRO
Antonarakis et al. (1995) reported this substitution in a patient with
less than 1% factor VIII activity and severe hemophilia A. The
substitution is caused by a CTG-to-CCG transition at codon 308 in exon 7
of the A1 domain, resulting in proline for leucine-308.
.0117
HEMOPHILIA A
F8, TRP323TER
In 1 patient with hemophilia A, Lin et al. (1993) identified a
TAT-to-TAA substitution at codon 323 in exon 8, resulting in a stop
codon.
.0118
HEMOPHILIA A
F8, CYS329TYR
Antonarakis et al. (1995) reported this substitution in a patient with
less than 1% factor VIII activity and severe hemophilia A. The
substitution is caused by a TGT-to-TAT transition at codon 329 in exon 8
of the A1 domain, resulting in tyrosine for cysteine-329.
.0119
HEMOPHILIA A
F8, CYS329SER
Antonarakis et al. (1995) reported that this substitution in a patient
with 2.6% factor VIII activity, 3.2% factor VIII antigen, and moderate
hemophilia A. The substitution is caused by a TGT-to-TCT transversion at
codon 329 in exon 8 of the A1 domain, resulting in serine for
cysteine-329.
.0120
HEMOPHILIA A
F8, 2-BP DEL, FS
In a patient with severe hemophilia A, Higuchi et al. (1990) identified
the deletion of 2 nucleotides (GA) resulting in a frameshift downstream
from codon 341 in exon 8.
.0121
HEMOPHILIA A
F8, SER373TER
In 1 patient with hemophilia A, Acquila et al. (1993) identified a
TCA-to-TAA substitution at codon 373 in exon 8, resulting in a stop
codon.
.0122
HEMOPHILIA A
F8, SER373LEU
Acquila et al. (1993) found this substitution in a patient with 8%
factor VIII activity and mild hemophilia A. The substitution is caused
by a TCA-to-TTA transition at codon 373 in exon 8, resulting in leucine
for serine-373. The mutation has been shown to abolish normal cleavage
by thrombin.
.0123
HEMOPHILIA A
F8, SER373PRO
Johnson et al. (1994) found this substitution in a patient with 10%
factor VIII activity, 100% factor VIII antigen, and mild hemophilia A.
The substitution is caused by a TCA-to-CCA transition at codon 373 in
exon 8, resulting in proline for serine-373. The mutation abolishes
normal cleavage by thrombin.
.0124
HEMOPHILIA A
F8, 2-BP DEL, FS
In a patient with severe hemophilia A, Antonarakis et al. (1995)
reported the deletion of 2 nucleotides (AA), resulting in a frameshift
downstream from codon 381-382 in exon 8.
.0125
HEMOPHILIA A
F8, ILE386SER
Lin et al. (1993) found this substitution in a patient with less than 1%
factor VIII activity and severe hemophilia A. The substitution is caused
by a ATT-to-AGT transversion at codon 386 in exon 8 of the A2 domain,
resulting in serine for isoleucine-386.
.0126
HEMOPHILIA A
F8, GLU390GLY
Antonarakis et al. (1995) reported this substitution in 2 patients with
less than 1-3.3% factor VIII activity and severe to moderate hemophilia
A. The substitution is caused by a GAG-to-GGG transition at codon 390 in
exon 8 of the A2 domain, resulting in glycine for glutamic acid-390.
.0127
HEMOPHILIA A
F8, LEU412PHE
Higuchi et al. (1991) found this substitution in 2 patients with 5-10.5%
factor VIII activity and moderate to mild hemophilia A. The substitution
is caused by a TTG-to-TTT transversion at codon 412 in exon 9 of the A2
domain, resulting in phenylalanine for leucine-412.
.0128
HEMOPHILIA A
F8, 1-BP DEL, FS
In a patient with severe hemophilia A, Lin et al. (1993) identified the
deletion of 1 nucleotide (G), resulting in a frameshift downstream from
leucine-412 in exon 9.
.0129
HEMOPHILIA A
F8, LYS425ARG
Higuchi et al. (1991) found this substitution in a patient with less
than 1% factor VIII activity, 5% factor VIII antigen, and severe
hemophilia A. The substitution is caused by a AAA-to-AGA transition at
codon 425 in exon 9 of the A2 domain, resulting in arginine for
lysine-425.
.0130
HEMOPHILIA A
F8, TYR431ASN
Pieneman et al. (1993) found this substitution in a patient with 4%
factor VIII activity and moderate hemophilia A. The substitution is
caused by a TAC-to-AAC transversion at codon 431 in exon 9 of the A2
domain, resulting in asparagine for tyrosine-431.
.0131
HEMOPHILIA A
F8, TYR473HIS
Higuchi et al. (1991) found this substitution in a patient with mild
hemophilia A. The substitution is caused by a TAT-to-CAT transition at
codon 473 in exon 10 of the A2 domain, resulting in histidine for
tyrosine-473.
.0132
HEMOPHILIA A
F8, TYR473CYS
Higuchi et al. (1991) found this substitution in 2 patients with
2.7-3.5% factor VIII activity and moderate hemophilia A. The
substitution is caused by a TAT-to-TGT transition at codon 473 in exon
10 of the A2 domain, resulting in cysteine for tyrosine-473.
.0133
HEMOPHILIA A
F8, ILE475THR
Antonarakis et al. (1995) reported this substitution in a patient with
5-5.7% factor VIII activity, 6.9-8.8% factor VIII antigen, and mild
hemophilia A. The substitution is caused by a ATC-to-ACC transition at
codon 475 in exon 10 of the A2 domain, resulting in threonine for
isoleucine-475.
.0134
HEMOPHILIA A
F8, GLY479ARG
Naylor et al. (1993) found this substitution in 3 patients with 2-17.8%
factor VIII activity, 31.6% factor VIII antigen, and moderate to mild
hemophilia A. The substitution is caused by a GGA-to-AGA transition at
codon 479 in exon 10 of the A2 domain, resulting in arginine for
glycine-479. The G-to-A transition follows the rule of CG-to-CA
mutations at CG dinucleotides.
.0135
HEMOPHILIA A
F8, 11-BP DEL, FS
In a patient with severe hemophilia A, Lin et al. (1993) identified the
deletion of 11 nucleotides (CCGTCCTTTGT) between codon 483 and 487 in
exon 10. The deletion results in a frameshift.
.0136
HEMOPHILIA A
F8, IVS10AS, G-T, +1
In a patient with mild hemophilia A, Economou et al. (1992) identified a
G-to-T transversion in codon 504. This mutation, which did not result in
amino acid substitution, occurs in the first nucleotide of exon 11 and
alters the sequence of the acceptor splice site of intron 10.
.0137
HEMOPHILIA A
F8, 1-BP INS, FS
In a patient with severe hemophilia A, Economou et al. (1992) identified
the insertion of 1 nucleotide (G), resulting in a frameshift downstream
from codon 513 or 514 in exon 11.
.0138
HEMOPHILIA A
F8, ASP525ASN
Antonarakis et al. (1995) reported this substitution in a patient with
6% factor VIII activity, 61% factor VIII antigen, and moderate
hemophilia A. The substitution is caused by a GAT-to-AAT transition at
codon 525 in exon 11 of the A2 domain, resulting in asparagine for
aspartic acid-525.
.0139
HEMOPHILIA A
F8, ARG527TRP
Higuchi et al. (1991) found this substitution in a patient with 9.5-38%
factor VIII activity, 43-245% factor VIII antigen, and mild hemophilia
A. The substitution is caused by a CGG-to-TGG transition at codon 527 in
exon 11 of the A2 domain, resulting in tryptophan for arginine-527. The
C-to-T transition follows the rule of CG-to-TG mutations at CG
dinucleotides. This mutation has also been found by others (McGinniss et
al., 1993; see also Antonarakis et al., 1995).
.0140
HEMOPHILIA A
F8, ARG531CYS
Higuchi et al. (1991) found this substitution in 3 patients with
4.2-6.7% factor VIII activity and moderate to mild hemophilia A. The
substitution is caused by a CGC-to-TGC transition at codon 531 in exon
11 of the A2 domain, resulting in cysteine for arginine-531. The C-to-T
transition follows the rule of CG-to-TG mutations at CG dinucleotides.
This mutation has also been found by others (Economou et al., 1992 and
Diamond et al., 1992).
.0141
HEMOPHILIA A
F8, ARG531GLY
Higuchi et al. (1991) found this substitution in a patient with 9.2%
factor VIII activity and mild hemophilia A. The substitution is caused
by a CGC-to-GGC transversion at codon 531 in exon 11 of the A2 domain,
resulting in glycine for arginine-531.
.0142
HEMOPHILIA A
F8, ARG531HIS
Antonarakis et al. (1995) reported this substitution in a patient with
23.5-32% factor VIII activity, 20-33.2% factor VIII antigen and mild
hemophilia A. The substitution is caused by a CGC-to-CAC transition at
codon 531 in exon 11 of the A2 domain, resulting in histidine for
arginine-531. The G-to-A transition follows the rule of CG-to-CA
mutations at CG dinucleotides.
.0143
HEMOPHILIA A
F8, SER535GLY
Antonarakis et al. (1995) reported this substitution in 2 patients with
mild hemophilia A. The substitution is caused by a AGT-to-GGT transition
at codon 535 in exon 11 of the A2 domain, resulting in glycine for
serine-535.
.0144
HEMOPHILIA A
F8, ASP542GLY
Higuchi et al. (1991) found this substitution in a patient with less
than 1% factor VIII activity, 5% factor VIII antigen, and severe
hemophilia A. The substitution is caused by a GAT-to-GGT transition at
codon 542 in exon 11 of the A2 domain, resulting in glycine for aspartic
acid-542.
.0145
HEMOPHILIA A
F8, GLU557TER
In a patient with hemophilia A, Diamond et al. (1992) identified a
GAA-to-TAA substitution at codon 557 in exon 11, resulting in a stop
codon.
.0146
HEMOPHILIA A
F8, SER558PHE
McGinniss et al. (1993) found this substitution in a patient with 21%
factor VIII activity, 175% factor VIII antigen, and mild hemophilia A.
The substitution is caused by a TCT-to-TTT transition at codon 558 in
exon 11 of the A2 domain, resulting in phenylalanine for serine-558.
.0147
HEMOPHILIA A
F8, GLN565LYS
Higuchi et al. (1991) found this substitution in 2 patients with 6.8%
factor VIII activity and moderate to mild hemophilia A. The substitution
is caused by a CAG-to-AAG transversion at codon 565 in exon 11 of the A2
domain, resulting in lysine for glutamine-565. This mutation has also
been found by others (Antonarakis et al., 1995).
.0148
HEMOPHILIA A
F8, SER577PRO
Reiner and Thompson (1992) found this substitution in 5 patients with
less than 1% factor VIII activity and severe hemophilia A. The
substitution is caused by a TCT-to-CCT transition at codon 577 in exon
12 of the A2 domain, resulting in proline for serine-577. The C-to-T
transition follows the rule of CG-to-TG mutations at CG dinucleotides.
This mutation has also been found by others (Antonarakis et al., 1995).
.0149
HEMOPHILIA A
F8, ARG583TER
In 5 patients with hemophilia A, Pattinson et al. (1990) identified a
CGA-to-TGA substitution at codon 583 in exon 12, resulting in a stop
codon. The C-to-T transition follows the rule of CG-to-TG mutations at
CG dinucleotides. This mutation has also been found by others (Reiner
and Thompson, 1992; see also Antonarakis et al., 1995).
.0150
HEMOPHILIA A
F8, SER584ILE
Antonarakis et al. (1995) reported this substitution in a patient with
hemophilia A. The substitution is caused by a AGC-to-ATC transversion at
codon 584 in exon 12 of the A2 domain, resulting in isoleucine for
serine-584.
.0151
HEMOPHILIA A
F8, TRP585CYS
Lin et al. (1993) found this substitution in a patient with less than 1%
factor VIII activity and severe hemophilia A. The substitution is caused
by a TGG-to-TGC transversion at codon 585 in exon 12 of the A2 domain,
resulting in cysteine for tryptophan-585.
.0152
HEMOPHILIA A
F8, TYR586SER
Lin et al. (1993) found this substitution in a patient with less than 1%
factor VIII activity and severe hemophilia A. The substitution is caused
by a TAC-to-TCC transversion at codon 586 in exon 12 of the A2 domain,
resulting in serine for tyrosine-586.
.0153
HEMOPHILIA A
F8, ARG593CYS
Higuchi et al. (1991) found this substitution in a patient with mild to
moderate hemophilia A. The substitution is caused by a CGC-to-TGC
transition at codon 593 in exon 12 of the A2 domain, resulting in
cysteine for arginine-593. The C-to-T transition follows the rule of
CG-to-TG mutations at CG dinucleotides. This mutation has also been
found by others (Naylor et al., 1993 and Diamond et al., 1992; see also
Antonarakis et al., 1995).
.0154
HEMOPHILIA A
F8, ASN612SER
Antonarakis et al. (1995) reported this substitution in a patient with
hemophilia A. The substitution is caused by a AAC-to-AGC transition at
codon 612 in exon 12 of the A2 domain, resulting in serine for
asparagine-612.
.0155
HEMOPHILIA A
F8, IVS12DS, G-A, +5
In a patient with mild hemophilia A, Antonarakis et al. (1995) reported
a G-to-A transition. The substitution is at the fifth nucleotide of the
donor splice site of intron 12 and results in abnormal splicing.
.0156
HEMOPHILIA A
F8, VAL634ALA
McGinniss et al. (1993) found this substitution in a patient with 5%
factor VIII activity, 138% factor VIII antigen, and mild hemophilia A.
The substitution is caused by a GTG-to-GCG transition at codon 634 in
exon 13 of the A2 domain, resulting in alanine for valine-634.
.0157
HEMOPHILIA A
F8, VAL634MET
McGinniss et al. (1993) found a val634-to-met substitution in 2 patients
with less than 1% factor VIII activity, 175% factor VIII antigen, and
severe hemophilia A. The substitution is caused by a GTG-to-ATG
transition at codon 634 in exon 13 of the A2 domain.
.0158
HEMOPHILIA A
F8, TYR636TER
In 2 patients with hemophilia A (1 with inhibitors), Antonarakis et al.
(1995) reported the substitution of TAC-to-TAG at codon 636 in exon 13,
resulting in a stop codon.
.0159
HEMOPHILIA A
F8, ALA644VAL
Higuchi et al. (1991) found this substitution in a patient with 14%
factor VIII activity, 25% factor VIII antigen, and mild hemophilia A.
The substitution is caused by a GCA-to-GTA transition at codon 644 in
exon 13 of the A2 domain, resulting in valine for alanine-644.
.0160
HEMOPHILIA A
F8, 3-BP DEL, PHE652DEL
In a patient with 1.4% factor VIII activity, 12% factor VIII antigen,
and severe hemophilia A, McGinniss et al. (1993) identified an in-frame
deletion of 3 bp corresponding to codon 652 (TTC) in exon 13 of the A2
domain, resulting in the deletion of phenylalanine-652.
.0161
HEMOPHILIA A
F8, PHE658LEU
Antonarakis et al. (1995) reported this substitution in a patient with
5.1% factor VIII activity, 50.5% factor VIII antigen and moderate
hemophilia A. The substitution is caused by a TTC-to-CTC transition at
codon 658 in exon 13 of the A2 domain, resulting in leucine for
phenylalanine-658.
.0162
HEMOPHILIA A
F8, ARG698TRP
Diamond et al. (1992) found this substitution in a patient with mild
hemophilia A. The substitution is caused by a CGG-to-TGG transition at
codon 698 in exon 14 of the A2 domain, resulting in tryptophan for
arginine-698. The C-to-T transition follows the rule of CG-to-TG
mutations at CG dinucleotides.
.0163
HEMOPHILIA A
F8, ALA704THR
Higuchi et al. (1991) found this substitution in 3 patients with a mild
to moderate hemophilia A. The substitution is caused by a GCC-to-ACC
transition at codon 704 in exon 14 of the A2 domain, resulting in
threonine for alanine-704. The G-to-A transition follows the rule of
CG-to-CA mutations at CG dinucleotides. See also Antonarakis et al.
(1995).
.0164
HEMOPHILIA A
F8, GLU720LYS
Antonarakis et al. (1995) reported this glu720-to-lys substitution in 2
patients with 12.5-30% factor VIII activity, less than 20% factor VIII
antigen, and a mild hemophilia A. The substitution is caused by a
GAG-to-AAG transition at codon 720 in exon 14 of the A2 domain. The
G-to-A transition follows the rule of CG-to-CA mutations at CG
dinucleotides.
.0165
HEMOPHILIA A
F8, ARG795TER
In a patient with hemophilia A, Pattinson et al. (1990) identified the
substitution of CGA-to-TGA at codon 795 in exon 14, resulting in a stop
codon. The C-to-T transition follows the rule of CG-to-TG mutations at
CG dinucleotides.
.0166
HEMOPHILIA A
F8, 1-BP INS, FS
In a patient with severe hemophilia A, Naylor et al. (1993) identified
the insertion of 1 nucleotide (A) at codon 961-2 or 3 in exon 14. The
mutation results in a frameshift.
.0167
HEMOPHILIA A
F8, 2-BP DEL, FS
In a patient with severe hemophilia A, Lin et al. (1993) identified the
deletion of 2 nucleotides (AG) that results in a frameshift downstream
from codon 969 in exon 14.
.0168
HEMOPHILIA A
F8, GLU1038LYS
Higuchi et al. (1991) and McGinniss et al. (1993) found this
substitution in a patient with 2.4% factor VIII activity, 15% factor
VIII antigen, and moderate hemophilia A. The substitution is caused by a
GAG-to-AAG transition at codon 1038 in exon 14 of the B domain,
resulting in lysine for glutamic acid-1038.
.0169
HEMOPHILIA A
F8, 2-BP DEL, FS
In a patient with severe hemophilia A, Lin et al. (1993) identified the
deletion of 2 nucleotides (AA) resulting in a frameshift downstream from
codon 1164 in exon 14.
.0170
HEMOPHILIA A
F8, 1-BP DEL, FS
In 2 patients with severe hemophilia A, Lin et al. (1993) identified the
deletion of 1 nucleotide (A) resulting in a frameshift downstream from
codon 1194 in exon 14.
.0171
HEMOPHILIA A
F8, 1-BP DEL, FS
In a patient with severe hemophilia A, Naylor et al. (1993) identified
the deletion of 1 nucleotide (C) resulting in a frameshift downstream
from codon 1212 in exon 14.
.0172
HEMOPHILIA A
F8, 2-BP, INS, FS
In a patient with severe hemophilia A, Lin et al. (1993) identified the
insertion of 2 nucleotides (AA) resulting in a frameshift downstream
from codon 1324 in exon 14.
.0173
HEMOPHILIA A
F8, 4-BP DEL, FS
In a patient with severe hemophilia A, Lin et al. (1993) identified the
deletion of 4 nucleotides (TAGA) resulting in a frameshift downstream
from codons 1355-6 in exon 14.
.0174
HEMOPHILIA A
F8, 1-BP INS, FS
In a patient with severe hemophilia A, Higuchi et al. (1991) identified
the insertion of 1 nucleotide (A) resulting in a frameshift downstream
from codon 1395 in exon 14.
.0175
HEMOPHILIA A
F8, 5-BP DEL, FS
Antonarakis et al. (1995) reported in a patient with severe hemophilia A
the deletion of 5 nucleotides (CTCTT) resulting in a frameshift
downstream from codons 1412-4 in exon 14.
.0176
HEMOPHILIA A
F8, 4-BP DEL, FS
In a patient with severe hemophilia A, Naylor et al. (1993) identified
the deletion of 4 nucleotides (AAGA) resulting in a frameshift
downstream from codons 1422-5 in exon 14.
.0177
HEMOPHILIA A
F8, 1-BP INS, FS
Higuchi et al. (1991) identified in 2 patients with severe hemophilia A
the insertion of 1 nucleotide (A) resulting in a frameshift downstream
from codons 1439, 1440 or 1441 in exon 14.
.0178
HEMOPHILIA A
F8, 1-BP DEL, FS
In 2 patients with severe hemophilia A, Higuchi et al. (1991) and Naylor
et al. (1993) identified the deletion of 1 nucleotide (A) resulting in a
frameshift downstream from codons 1439, 1440 or 1441 in exon 14.
.0179
HEMOPHILIA A
F8, 2-BP DEL, FS
In a patient with severe hemophilia A, Higuchi et al. (1991) identified
the deletion of 2 nucleotides (GA) resulting in a frameshift downstream
from codons 1535-6 in exon 14.
.0180
HEMOPHILIA A
F8, 1-BP INS, FS
In a patient with severe hemophilia A, Lin et al. (1993) identified the
insertion of 1 nucleotide (A) resulting in a frameshift downstream from
codon 1590 in exon 14.
.0181
HEMOPHILIA A
F8, 1-BP DEL, FS
In a patient with severe hemophilia A, Lin et al. (1993) identified the
deletion of 1 nucleotide (C) resulting in a frameshift downstream from
codon 1601 in exon 14.
.0182
HEMOPHILIA A
F8, GLU161TER
In a patient with hemophilia A, Lavergne et al. (1992) identified the
substitution of GAG-to-TAG at codon 1615 in exon 14, resulting in a stop
codon.
.0183
HEMOPHILIA A
F8, ARG1689HIS
Schwaab et al. (1993) found this substitution in 3 patients with 7-11%
factor VIII activity, 130-165% factor VIII antigen, and mild hemophilia
A. The substitution is caused by a CGC-to-CAC transition at codon 1689
in exon 14 of the A3 domain, resulting in histidine for arginine-1689.
The G-to-A transition follows the rule of CG-to-CA mutations at CG
dinucleotides. The mutation has been shown to abolish normal cleavage by
thrombin at the light chain.
.0184
HEMOPHILIA A
F8, ARG1696TER
In 2 patients with hemophilia A and inhibitors, Pattinson et al. (1990)
identified the substitution of CGA to TGA at codon 1696 in exon 14,
resulting in a stop codon. The C-to-T transition follows the rule of
CG-to-TG mutations at CG dinucleotides. This mutation has also been
found by others (Naylor et al., 1993).
.0185
HEMOPHILIA A
F8, ARG1696GLY
Reiner and Thompson (1992) found this substitution in a patient with 17%
factor VIII activity and mild hemophilia A. The substitution was caused
by a CGA-to-TGA transition at codon 1696 in exon 14 of the A3 domain,
resulting in glycine for arginine-1696. The C-to-T transition follows
the rule of CG-to-TG mutations at CG dinucleotides.
.0186
HEMOPHILIA A
F8, IVS14AS, A-G, -2
In a patient with less than 1% factor VIII activity, less than 2.5%
factor VIII antigen, and severe hemophilia A, Antonarakis et al. (1995)
reported the substitution of A to G at the second nucleotide of the
acceptor splice site of intron 14, resulting in abnormal splicing.
.0187
HEMOPHILIA A
F8, GLY1750ARG
Antonarakis et al. (1995) reported this substitution in 4 patients with
21-26% factor VIII activity, 14.5-26% factor VIII antigen, and mild
hemophilia A. The substitution was caused by a GGA-to-AGA transition at
codon 1750 in exon 15 of the A3 domain, resulting in arginine for
glycine-1750.
.0188
HEMOPHILIA A
F8, LEU1756VAL
Antonarakis et al. (1995) reported this substitution in a patient with
5% factor VIII activity, 1.5% factor VIII antigen, and moderate
hemophilia A. The substitution was caused by a TTG-to-GTG transversion
at codon 1756 in exon 15 of the A3 domain, resulting in valine for
leucine-1756.
.0189
HEMOPHILIA A
F8, LEU1756PHE
Antonarakis et al. (1995) reported this substitution in a patient with
18.5% factor VIII activity and mild hemophilia A. The substitution was
caused by a TTG-to-TTC transversion at codon 1756 in exon 15 of the A3
domain, resulting in phenylalanine for leucine-1756.
.0190
HEMOPHILIA A
F8, GLY1760GLU
Lin et al. (1993) found this substitution in a patient with less than 1%
factor VIII activity and severe hemophilia A. The substitution was
caused by a GGG-to-GAG transition at codon 1760 in exon 15 of the A3
domain, resulting in glutamic acid for glycine-1760.
.0191
HEMOPHILIA A
F8, ARG1781HIS
Higuchi et al. (1991) found this substitution in 4 patients with 2-2.5%
factor VIII activity, 4.7-5.4% factor VIII antigen, and moderate
hemophilia A. The substitution was caused by a CGT-to-CAT transition at
codon 1781 in exon 16 of the A3 domain, resulting in histidine for
arginine-1781. The G-to-A transition follows the rule of CG-to-CA
mutations at CG dinucleotides. See also Antonarakis et al. (1995).
.0192
HEMOPHILIA A
F8, ARG1781CYS
Jonsdottir et al. (1992) found this substitution in a patient with 4-7%
factor VIII activity and mild hemophilia A. The substitution was caused
by a CGT-to-TGT transition at codon 1781 in exon 16 of the A3 domain,
resulting in cysteine for arginine-1781. The C-to-T transition follows
the rule of CG-to-TG mutations at CG dinucleotides.
.0193
HEMOPHILIA A
F8, ARG1781GLY
Antonarakis et al. (1995) reported this substitution in a patient with
6% factor VIII activity and mild hemophilia A. The substitution was
caused by a CGT-to-GGT transversion at codon 1781 in exon 16 of the A3
domain, resulting in glycine for arginine-1781.
.0194
HEMOPHILIA A
F8, SER1784TYR
Higuchi et al. (1991) found this substitution in a patient with less
than 1% factor VIII activity and clinically a severe hemophilia A. The
substitution was caused by a TCC-to-TAC transversion at codon 1784 in
exon 16 of the A3 domain, resulting in tyrosine for serine-1784.
.0195
HEMOPHILIA A
F8, LEU1789PHE
Diamond et al. (1992) and Lin et al. (1993) found this substitution in 3
patients with 7.2% factor VIII activity and mild hemophilia A. The
substitution was caused by a CTT-to-TTT transition at codon 1789 in exon
16 of the A3 domain, resulting in phenylalanine for leucine-1789.
.0196
HEMOPHILIA A
F8, GLN1796TER
In a patient with hemophilia A and inhibitors, Lin et al. (1993)
identified the substitution of CAG-to-TAG at codon 1796 in exon 16,
resulting in a stop codon.
.0197
HEMOPHILIA A
F8, MET1823ILE
Lin et al. (1993) found this substitution in a patient with 4.6% factor
VIII activity and moderate hemophilia A. The substitution is caused by a
ATG-to-ATA transition at codon 1823 in exon 16 of the A3 domain,
resulting in isoleucine for methionine-1823.
.0198
HEMOPHILIA A
F8, PRO1825SER
Higuchi et al. (1991) found this substitution in a patient with 15%
factor VIII activity and mild hemophilia A. The substitution was caused
by a CCC-to-TCC transition at codon 1825 in exon 16 of the A3 domain,
resulting in serine for proline-1825.
.0199
HEMOPHILIA A
F8, THR1826PRO
Economou et al. (1992) found this substitution in a patient with mild
hemophilia A. The substitution was caused by a ACT-to-CCT transversion
at codon 1826 in exon 16 of the A3 domain, resulting in proline for
threonine-1826.
.0200
HEMOPHILIA A
F8, LYS1827TER
In 2 patients with hemophilia A and inhibitors, Lin et al. (1993)
identified the mutation AAA to TAA at codon 1827 in exon 16, resulting
in a stop codon.
.0201
HEMOPHILIA A
F8, ALA1834VAL
Lin et al. (1993) found this substitution in a patient with 18% factor
VIII activity and mild hemophilia A. The substitution was caused by a
GCC-to-GTC transition at codon 1834 in exon 16 of the A3 domain,
resulting in valine for alanine-1834.
.0202
HEMOPHILIA A
F8, IVS16DS, G-A, -1
In 2 patients with 9-18% factor VIII activity, 5.9% factor VIII antigen,
and mild hemophilia A, Higuchi et al. (1991) and Antonarakis et al.
(1995) reported a G-to-A substitution at the -1 nucleotide of the donor
splice site of intron 16, resulting in abnormal splicing.
.0203
HEMOPHILIA A
F8, ASP1846ASN
Antonarakis et al. (1995) reported this substitution in a patient with
less than 1% factor VIII activity and severe hemophilia A. The
substitution was caused by a GAT-to-AAT transition at codon 1846 in exon
17 of the A3 domain, resulting in asparagine for aspartic acid-1846.
.0204
HEMOPHILIA A
F8, ASP1846TYR
Antonarakis et al. (1995) reported this substitution in a patient with
less than 1% factor VIII activity and severe hemophilia A. The
substitution was caused by a GAT-to-TAT transversion at codon 1846 in
exon 17 of the A3 domain, resulting in tyrosine for aspartic acid-1846.
.0205
HEMOPHILIA A
F8, HIS1848ARG
Higuchi et al. (1991) found this substitution in a patient with 1-5%
factor VIII activity and moderate hemophilia A. The substitution was
caused by a CAC-to-CGC transition at codon 1848 in exon 17 of the A3
domain, resulting in arginine for histidine-1848.
.0206
HEMOPHILIA A
F8, PRO1854ARG
Antonarakis et al. (1995) reported this substitution in a patient with
less than 1% factor VIII activity and severe hemophilia A. The
substitution was caused by a CCC-to-CGC transversion at codon 1854 in
exon 17 of the A3 domain, resulting in arginine for proline-1854.
.0207
HEMOPHILIA A
F8, 1-BP INS, FS
Antonarakis et al. (1995) reported in 1 patient with severe hemophilia A
the insertion of 1 nucleotide (T) resulting in a frameshift downstream
from codon 1855 in exon 17.
.0208
HEMOPHILIA A
F8, GLN1874TER
In 1 patient with hemophilia A and inhibitors, Naylor et al. (1993)
identified the substitution of CAG-to-TAG at codon 1874 in exon 17,
resulting in a stop codon.
.0209
HEMOPHILIA A
F8, GLU1885LYS
Lin et al. (1993) found this substitution in a patient with less than 1%
factor VIII activity and severe hemophilia A. The substitution was
caused by a GAG-to-AAG transition at codon 1885 in exon 17 of the A3
domain, resulting in lysine for glutamic acid-1885.
.0210
HEMOPHILIA A
F8, 1-BP INS, FS
Higuchi et al. (1991) identified in 1 patient with severe hemophilia A
the insertion of 1 nucleotide (A) resulting in a frameshift downstream
from codon 1888 in exon 17.
.0211
HEMOPHILIA A
F8, ASN1922SER
Higuchi et al. (1991) and Diamond et al. (1992) found this substitution
in 2 patients with less than 1% factor VIII activity and
severe-to-moderate hemophilia A. The substitution was caused by a
AAT-to-AGT transition at codon 1922 in exon 18 of the A3 domain,
resulting in serine for asparagine-1922.
.0212
HEMOPHILIA A
F8, ARG1941LEU
Nafa et al. (1992) found this substitution in a patient with 7% factor
VIII activity and moderate hemophilia A. The substitution was caused by
a CGA-to-CTA transversion at codon 1941 in exon 18 of the A3 domain,
resulting in leucine for arginine-1941.
.0213
HEMOPHILIA A
F8, TRP1942TER
In a patient with hemophilia A, Lin et al. (1993) identified the
substitution of TGG-to-TAG at codon 1942 in exon 18, resulting in a stop
codon.
.0214
HEMOPHILIA A
F8, GLY1948ASP
David et al. (1994) found this substitution in a patient with 7.4%
factor VIII activity, 46.7% factor VIII antigen, and moderate hemophilia
A. The substitution was caused by a GGC-to-GAC transition at codon 1948
in exon 18 of the A3 domain, resulting in aspartic acid for
glycine-1948.
.0215
HEMOPHILIA A
F8, GLY1960VAL
Antonarakis et al. (1995) reported this substitution in a patient with
6% factor VIII activity and moderate hemophilia A. The substitution was
caused by a GGA-to-GTA transversion at codon 1960 in exon 18 of the A3
domain, resulting in valine for glycine-1960.
.0216
HEMOPHILIA A
F8, HIS1961TYR
Antonarakis et al. (1995) reported this substitution in a patient with
15.5% factor VIII activity, 7.8% factor VIII antigen, and mild
hemophilia A. The substitution was caused by a CAT-to-TAT transition at
codon 1961 in exon 18 of the A3 domain, resulting in tyrosine for
histidine-1961.
.0217
HEMOPHILIA A
F8, ARG1966TER
In 7 patients with hemophilia A (3 with inhibitors), Reiner and Thompson
(1992) identified the substitution of CGA to TGA at codon 1966 in exon
18, resulting in a stop codon. The C-to-T transition follows the rule of
CG-to-TG mutations at CG dinucleotides. This mutation has also been
found by others (Lin et al., 1993; Naylor et al., 1993; Schwaab et al.,
1993; and David et al., 1994).
.0218
HEMOPHILIA A
F8, 1-BP DEL, FS
Antonarakis et al. (1995) identified in 2 patients with severe
hemophilia A the deletion of 1 nucleotide (A) resulting in a frameshift
downstream from codon 1967-1968 in exon 19.
.0219
HEMOPHILIA A
F8, 1-BP DEL, FS
Antonarakis et al. (1995) reported in 1 patient with severe hemophilia A
the deletion of 1 nucleotide (G) resulting in a frameshift downstream
from codon 1998 in exon 19.
.0220
HEMOPHILIA A
F8, GLU1987TER, EX19 DEL
In 1 patient with hemophilia A, Naylor et al. (1993) identified the
substitution of GAA to TAA at codon 1987 in exon 19, resulting in a stop
codon and exon 19 skipping.
.0221
HEMOPHILIA A
F8, ARG1997TRP
Higuchi et al. (1991) and Antonarakis et al. (1995) reported this
substitution in 3 patients with less than 1-3.4% factor VIII activity
and moderate to severe hemophilia A. The substitution was caused by a
CGG-to-TGG transition at codon 1997 in exon 19 of the A3 domain,
resulting in tryptophan for arginine-1997. The C-to-T transition follows
the rule of CG-to-TG mutations at CG dinucleotides.
.0222
HEMOPHILIA A
F8, ASN2019SER
Antonarakis et al. (1995) reported this substitution in a patient with
5% factor VIII activity, 3.3% factor VIII antigen, and moderate
hemophilia A. The substitution was caused by a AAT-to-AGT transition at
codon 2019 in exon 19 of the A3 domain, resulting in serine for
asparagine-2019.
.0223
HEMOPHILIA A
F8, TRP2046ARG
Diamond et al. (1992) found this substitution in a patient with moderate
hemophilia A. The substitution was caused by a TGG-to-CGG transition at
codon 2046 in exon 21 of the C1 domain, resulting in arginine for
tryptophan-2046.
.0224
HEMOPHILIA A
F8, SER2069PHE
Antonarakis et al. (1995) reported this substitution in a patient with
less than 1% factor VIII activity and severe hemophilia A. The
substitution was caused by a TCT-to-TTT transition at codon 2069 in exon
21 of the C1 domain, resulting in phenylalanine for serine-2069.
.0225
HEMOPHILIA A
F8, ASP2074GLY
Antonarakis et al. (1995) found this substitution in 2 patients with
4.5-9% factor VIII activity, 1.7-15.2% factor VIII antigen, and mild
hemophilia A. The substitution was caused by a GAT-to-GGT transition at
codon 2074 in exon 22 of the C1 domain, resulting in glycine for
aspartic acid-2074.
.0226
HEMOPHILIA A
F8, PHE2101LEU
Antonarakis et al. (1995) reported this substitution in 2 patients with
7-11% factor VIII activity, 5.3% factor VIII antigen, and mild
hemophilia A. The substitution was caused by a TTT-to-TTG transversion
at codon 2101 in exon 22 of the C1 domain, resulting in leucine for
phenylalanine-2101.
.0227
HEMOPHILIA A
F8, CYS2105TYR
Naylor et al. (1993) found this substitution in a patient with 14%
factor VIII activity and mild hemophilia A. The substitution was caused
by a TAT-to-TGT transition at codon 2105 in exon 22 of the C1 domain,
resulting in cysteine for tyrosine-2105.
.0228
HEMOPHILIA A
F8, SER2119TYR
Antonarakis et al. (1995) reported this substitution in 3 patients with
3-8% factor VIII activity, 9.2-13.2% factor VIII antigen, and mild to
moderate hemophilia A. The substitution was caused by a TCC-to-TAC
transversion at codon 2119 in exon 22 of the C1 domain, resulting in
tyrosine for serine-2119.
.0229
HEMOPHILIA A
F8, 2-BP DEL, FS
Antonarakis et al. (1995) identified in 1 patient with severe hemophilia
A the deletion of 2 nucleotides (TC) resulting in a frameshift
downstream from serine-2119 in exon 22.
.0230
HEMOPHILIA A
F8, 2-BP DEL, FS
Higuchi et al. (1991) identified in 1 patient with severe hemophilia A
the deletion of 2 nucleotides (AA) resulting in a frameshift downstream
from codon 2136 in exon 23.
.0231
HEMOPHILIA A
F8, ARG2150HIS
Higuchi et al. (1991) found this substitution in 10 patients with less
than 1-7% factor VIII activity and severe-to-mild hemophilia A. The
substitution was caused by a CGT-to-CAT transition at codon 2150 in exon
23 of the C1 domain, resulting in histidine for arginine-2150. The
G-to-A transition follows the rule of CG-to-CA mutations at CG
dinucleotides. This mutation has also been reported by others (Naylor et
al., 1993; Diamond et al., 1992; Jonsdottir et al., 1992; and
Antonarakis et al., 1995).
.0232
HEMOPHILIA A
F8, PRO2153GLN
Antonarakis et al. (1995) reported this substitution in a patient with
3% factor VIII activity, 5.6% factor VIII antigen, and moderate
hemophilia A. The substitution was caused by a CCA-to-CAA transversion
at codon 2153 in exon 23 of the C1 domain, resulting in glutamine for
proline-2153.
.0233
HEMOPHILIA A
F8, THR2154ILE
Jonsdottir et al. (1992) found this substitution in a patient with 6%
factor VIII activity and mild hemophilia A. The substitution was caused
by a ACT-to-ATT transition at codon 2154 in exon 23 of the C1 domain,
resulting in isoleucine for threonine-2154.
.0234
HEMOPHILIA A
F8, ARG2159CYS
Higuchi et al. (1991) found this substitution in 12 patients with 6-26%
factor VIII activity, less than 5-15.7% factor VIII antigen, and mild
hemophilia A. The substitution was caused by a CGC-to-TGC transition at
codon 2159 in exon 23 of the C1 domain, resulting in cysteine for
arginine-2159. The C-to-T transition follows the rule of CG-to-TG
mutations at CG dinucleotides. This mutation has also been reported by
others (Naylor et al., 1993; McGinniss et al., 1993; Diamond et al.,
1992; Jonsdottir et al., 1992; and Antonarakis et al., 1995).
.0235
HEMOPHILIA A
F8, ARG2159LEU
Antonarakis et al. (1995) reported this substitution in a patient with
12% factor VIII activity, 4.8% factor VIII antigen, and mild hemophilia
A. The substitution was caused by a CGC-to-CTC transversion at codon
2159 in exon 23 of the C1 domain, resulting in leucine for
arginine-2159.
.0236
HEMOPHILIA A
F8, ARG2159HIS
Antonarakis et al. (1995) reported this substitution in a patient with
22% factor VIII activity, 11.9% factor VIII antigen, and mild hemophilia
A. The substitution was caused by a CGC-to-CAC transition at codon 2159
in exon 23 of the C1 domain, resulting in histidine for arginine-2159.
The G-to-A transition follows the rule of CG-to-CA mutations at CG
dinucleotides.
.0237
HEMOPHILIA A
F8, ARG2163HIS
Antonarakis et al. (1995) reported this substitution in 2 patients with
5% factor VIII antigen and moderate hemophilia A. The substitution was
caused by a CGC-to-CAC transition at codon 2163 in exon 23 of the C1
domain, resulting in histidine for arginine-2163.
.0238
HEMOPHILIA A
F8, ARG2163CYS
Reiner et al. (1992) found this substitution in a patient with 1% factor
VIII activity, less than 10% factor VIII antigen, and moderate
hemophilia A. The substitution was caused by a CGC-to-TGC transition at
codon 2163 in exon 23 of the C1 domain, resulting in cysteine for
arginine-2163. The C-to-T transition follows the rule of CG-to-TG
mutations at CG dinucleotides.
.0239
HEMOPHILIA A
F8, ALA2192PRO
Lin et al. (1993) found this substitution in a patient with 1% factor
VIII activity and moderate hemophilia A. The substitution was caused by
a GCT-to-CCT transversion at codon 2192 in exon 24 of the C2 domain,
resulting in proline for alanine-2192.
.0240
HEMOPHILIA A
F8, 3-BP DEL, PRO220 DEL
In 3 patients with less than 1% factor VIII activity and
severe-to-moderate hemophilia A, Economou et al. (1992) and Lin et al.
(1993) identified an in-frame deletion of 3-bp corresponding to codon
2205 (TctcCT) in exon 24 of the C2 domain, resulting in the deletion of
proline-2205.
.0241
HEMOPHILIA A
F8, ARG2209LEU
Millar et al. (1991) found this substitution in a patient with 3% factor
VIII activity, 2.5% factor VIII antigen, and moderate hemophilia A. The
substitution was caused by a CGA-to-CTA transversion at codon 2209 in
exon 24 of the C2 domain, resulting in leucine for arginine-2209.
.0242
HEMOPHILIA A
F8, ARG2209GLY
Antonarakis et al. (1995) reported this substitution in a patient with
less than 1% factor VIII activity and severe hemophilia A. The
substitution was caused by a CGA-to-GGA transversion at codon 2209 in
exon 24 of the C2 domain, resulting in glycine for arginine-2209.
.0243
HEMOPHILIA A
F8, 1-BP DEL, FS
Antonarakis et al. (1995) reported in 1 patient with severe hemophilia A
the deletion of 1 nucleotide (G) resulting in a frameshift downstream
from codon 2214 in exon 24.
.0244
HEMOPHILIA A
F8, TRP2229CYS
Naylor et al. (1991) and Diamond et al. (1992) found this substitution
in 2 patients with 3% factor VIII activity, moderate hemophilia A, and
inhibitors in 1 out of the 2. The substitution was caused by a
TGG-to-TGT transversion at codon 2229 in exon 25 of the C2 domain,
resulting in cysteine for tryptophan-2229.
.0245
HEMOPHILIA A
F8, GLN2246ARG
Antonarakis et al. (1995) reported this substitution in a patient with
4.5% factor VIII activity, 1.1% factor VIII antigen, and moderate
hemophilia A. The substitution was caused by a CAG-to-CGG transition at
codon 2246 in exon 25 of the C2 domain, resulting in arginine for
glutamine-2246.
.0246
HEMOPHILIA A
F8, 2-BP DEL, FS
Lin et al. (1993) identified in 1 patient with severe hemophilia A the
deletion of 2 nucleotides (AG) resulting in a frameshift downstream from
glutamine-2246 in exon 25.
.0247
HEMOPHILIA A
F8, GLN2270TER
In 1 patient with hemophilia A, Antonarakis et al. (1995) reported the
substitution of CAG-to-TAG at codon 2270 in exon 25, resulting in a stop
codon.
.0248
HEMOPHILIA A
F8, 5-BP DEL, FS
Antonarakis et al. (1995) reported in 1 patient with severe hemophilia A
the deletion of 5 nucleotides (AAATC) resulting in a frameshift
downstream from codon 2285-86 or 87 in exon 26.
.0249
HEMOPHILIA A
F8, PRO2300LEU
Higuchi et al. (1991) found this substitution in a patient with 7.5%
factor VIII activity and mild hemophilia A. The substitution was caused
by a CCG-to-CTG transition at codon 2300 in exon 26 of the C2 domain,
resulting in leucine for proline-2300. The C-to-T transition follows the
rule of CG-to-TG mutations at CG dinucleotides.
.0250
HEMOPHILIA A
F8, ARG2304CYS
Higuchi et al. (1991) and Reiner et al. (1992) found this substitution
in 2 patients with less than 1% factor VIII activity, less than 10%
factor VIII antigen, and severe hemophilia A. The substitution was
caused by a CGC-to-TGC transition at codon 2304 in exon 26 of the C2
domain, resulting in cysteine for arginine-2304. The C-to-T transition
follows the rule of CG-to-TG mutations at CG dinucleotides.
.0251
HEMOPHILIA A
F8, ARG2304HIS
Antonarakis et al. (1995) reported this substitution in a patient with
mild hemophilia A. The substitution was caused by a CGC-to-CAC
transition at codon 2304 in exon 26 of the C2 domain, resulting in
histidine for arginine-2304. The G-to-A transition follows the rule of
CG-to-CA mutations at CG dinucleotides.
.0252
HEMOPHILIA A
F8, EX1-6DEL
In a patient with severe hemophilia A (patient H238) and factor VIII
inhibitors, Millar et al. (1990) found a deletion of exons 1-6 of the
factor VIII gene.
.0253
HEMOPHILIA A
F8, EX2-4DEL
In a patient with severe hemophilia A (patient TWN11) and factor VIII
inhibitors, Lin et al. (1993) found a deletion of exons 2-4 of the
factor VIII gene.
.0254
HEMOPHILIA A
F8, EX3-5DEL
In a patient with severe hemophilia A (patient H151), Millar et al.
(1990) found a deletion of exons 3-5 of the factor VIII gene.
.0255
HEMOPHILIA A
F8, EX4-10DEL
In a patient with severe hemophilia A (patient TWN27) and factor VIII
inhibitors, Lin et al. (1993) found a deletion of exons 4-10 of the
factor VIII gene.
.0256
HEMOPHILIA A
F8, EX5-13DEL
In a patient with severe hemophilia A (patient H571) and factor VIII
inhibitors, Millar et al. (1990) found a deletion of exons 5-13 of the
factor VIII gene.
.0257
HEMOPHILIA A
F8, EX10DEL
In a patient with severe hemophilia A (patient 149), Krepelova et al.
(1992) found a deletion of exon 10 of the factor VIII gene.
.0258
HEMOPHILIA A
F8, EX14-21DEL
In a patient with severe hemophilia A (patient H229) and factor VIII
inhibitors, Millar et al. (1990) found a deletion of exons 14-21 of the
factor VIII gene.
.0259
HEMOPHILIA A
F8, EX14-22DEL
In a patient with severe hemophilia A (patient H20) and factor VIII
inhibitors, Nafa et al. (1990) found a deletion of exons 14-22 of the
factor VIII gene. See also Antonarakis et al. (1995).
.0260
HEMOPHILIA A
F8, EX15-22DEL
Antonarakis et al. (1995) reported 3 patients with severe hemophilia A
who had a deletion of exons 15-22 of the factor VIII gene.
.0261
HEMOPHILIA A
F8, EX16-26DEL
In a patient with severe hemophilia A (patient HDX3) and factor VIII
inhibitors, Figueiredo et al. (1992) found a deletion of exons 16-26 of
the factor VIII gene.
.0262
HEMOPHILIA A
F8, EX18-19DEL
In a patient with severe hemophilia A (patient 5b), Grover et al. (1987)
found a deletion of exons 18-19 of the factor VIII gene. This deletion
may extend to exon 22.
.0263
HEMOPHILIA A
F8, EX16DEL
In a patient with severe hemophilia A (patient HD10), Schwaab et al.
(1993) found a deletion of exon 16 of the factor VIII gene.
.0264
HEMOPHILIA A
F8, EX19-21DEL
In a patient with severe hemophilia A (patient H58) and factor VIII
inhibitors, Millar et al. (1990) found a deletion of exons 19-21 of the
factor VIII gene.
.0265
HEMOPHILIA A
F8, EX23-24DEL
In a patient with severe hemophilia A (patient HA711), Lavergne et al.
(1992) found a deletion of exons 23-24 of the factor VIII gene.
.0266
HEMOPHILIA A
F8, EX23-26DEL
In a patient with severe hemophilia A (patient HDX2) and factor VIII
inhibitors, Din et al. (1986) found a deletion of exons 23-26 of the
factor VIII gene. See also Lavergne et al. (1992).
.0267
HEMOPHILIA A
F8, 1-BP DEL
Favier et al. (2000) described a 14-month-old girl with severe
hemophilia A. Both of her parents had normal values of factor VIII
activity, and von Willebrand disease was excluded. Karyotype analysis
demonstrated no obvious alteration, and no F8 gene inversions were
found. Direct sequencing of the F8 gene exons revealed a frameshift-stop
mutation (Q565delC/ter566) in the heterozygous state in the proposita
only. F8 gene polymorphism analysis indicated that the mutation must
have occurred de novo in the paternal germline. Furthermore, analysis of
the pattern of X chromosome methylation at the human androgen receptor
gene locus demonstrated a skewed inactivation of the derived maternal X
chromosome from the lymphocytes of the proband's DNA. Thus, the severe
hemophilia A in the proposita resulted from a de novo F8 gene mutation
on the paternally derived X chromosome, associated with a nonrandom
pattern of inactivation of the maternally derived X chromosome.
.0268
HEMOPHILIA A
F8, CYS179GLY
In 2 brothers with severe hemophilia A, Mazurier et al. (2002) found a
T-to-G transversion in exon 4 of the F8C gene, resulting in a
cys179-to-gly (C179G) mutation. This mutation affected a cysteine
residue in the F8A1 domain that is conserved in the sequences of the
murine, canine, and swine factor 8 genes. A maternal first cousin showed
factor VIII deficiency. However, further study demonstrated that she was
a compound heterozygote for 2 mutations in the von Willebrand disease
gene (VWD; 193400).
.0269
HEMOPHILIA A
F8, TYR16CYS
Valleix et al. (2002) described an A-to-G transition in exon 1 of the F8
gene in monozygotic twin females that caused a tyr16-to-cys (Y16C)
mutation. Both twins were heterozygous for the mutation, which caused
severe hemophilia A in 1 and mild phenotype in the other. The mutation
was not present in the twins' healthy sister or parents, suggesting that
it had occurred de novo in the germline of 1 parent.
.0270
HEMOPHILIA A
F8, ALU INS
Sukarova et al. (2001) described a family with a severe form of
hemophilia A in which they identified an Alu retrotransposition event in
a coding exon, which represented the first report of an Alu insertion in
the F8 gene. The propositus was an 18-year-old Bulgarian boy in whom the
diagnosis of severe hemophilia had been made at the age of 1 year. His
12-year-old brother was also affected. There was no other family history
of the disorder. The 341-bp element incorporated into the F8C gene
interrupted the reading frame of the mature protein at met1224,
resulting in a stop codon within the inserted sequence. Sequence
analysis showed that the inserted fragment was a full Alu repeat
belonging to the Yb8 subfamily of Alu repetitive sequences, according to
the standardized nomenclature for Alu repeats (Batzer et al., 1996). The
mutation site was flanked by a 5-bp (AAGAA) direct repeat which Sukarova
et al. (2001) stated was the shortest direct repeat described at the
integration points of Alu insertions.
Ganguly et al. (2003) reported a second instance: a 6-year-old male in
whom an Alu element was inserted at position -19 of intron 18 of the F8C
gene, causing skipping of exon 19 and hemophilia A. The insertion, which
did not affect the natural splice donor site, was in the opposite
orientation with respect to the direction of transcription of the F8
gene. The size of intron 18 was predicted to be increased by
approximately 331 nucleotides because of the insertion.
See Also:
Aly et al. (1992); Antonarakis et al. (1985); Antonarakis et al. (1987);
Arrants et al. (1962); Barrow and Graham (1973); Bennett and Ratnoff
(1974); Bennett and Huehns (1970); Bloom and Peake (1977); Chediak
et al. (1980); Dombroski et al. (1991); Edgell et al. (1978); Firshein
et al. (1979); Gitschier et al. (1985); Graham et al. (1985); Gralnick
and Coller (1976); Green et al. (1991); Grozdea et al. (1969); Hemker
et al. (1980); Hoyer (1981); Jaffe and Nachman (1975); Kitchens
(1980); Klein et al. (1977); Lawn (1985); Levinson et al. (1990);
Marchesi et al. (1972); McKusick (1962); Mibashan et al. (1980);
Millar et al. (1990); Mori et al. (1979); Myers et al. (1985); Nilsson
et al. (1966); Nilsson et al. (1962); Oberle et al. (1985); Peake
et al. (1985); Ratnoff (1978); Roberts (1971); Rosendaal et al.
(1990); Saiki et al. (1985); Schiffman and Rapaport (1966); Seligsohn
et al. (1979); Tuddenham et al. (1981); Woolf (1962); Youssoufian
et al. (1987); Youssoufian et al. (1988); Youssoufian et al. (1988);
Zimmerman et al. (1971)
References:
1. Abrams, E. S.; Murdaugh, S. E.; Lerman, L. S.: Comprehensive detection
of single base changes in human genomic DNA using denaturing gradient
gel electrophoresis and a GC clamp. Genomics 7: 463-475, 1990.
2. Acquila, M.; Caprino, D.; Pecorara, M.; Baudo, F.; Morfini, M.;
Mori, P. G.: Two novel mutations at 373 codon of FVIII gene detected
by DGGE. Thromb. Haemost. 69: 392-393, 1993.
3. Alexander, B.; Goldstein, R.: Dual hemostatic defect in pseudohemophilia.
(Abstract) J. Clin. Invest. 32: 551 only, 1953.
4. Aly, A. M.; Arai, M.; Hoyer, L. W.: Cysteamine enhances the procoagulant
activity of factor VIII-East Hartford, a dysfunctional protein due
to a light chain thrombin cleavage site mutation (arginine-1689 to
cysteine). J. Clin. Invest. 89: 1375-1381, 1992.
5. Aly, A. M.; Higuchi, M.; Kasper, C. K.; Kazazian, H. H., Jr.; Antonarakis,
S. E.; Hoyer, L. W.: Hemophilia A due to mutations that create new
N-glycosylation sites. Proc. Nat. Acad. Sci. 89: 4933-4937, 1992.
6. Aly, A. M.; Hoyer, L. W.: Factor VIII-East Hartford (arginine1689
to cysteine) has procoagulant activity when separated from von Willebrand
factor. J. Clin. Invest. 89: 1382-1387, 1992.
7. Antonarakis, S. E.; Copeland, K. L.; Carpenter, R. J., Jr.; Carta,
C. A.; Hoyer, L. W.; Caskey, C. T.; Toole, J. J.; Kazazian, H. H.,
Jr.: Prenatal diagnosis of haemophilia A by factor VIII gene analysis. Lancet 32 5:
1407-1409, 1985. Note: Originally Volume I.
8. Antonarakis, S. E.; Kazazian, H. H.; Tuddenham, G. D.: Molecular
etiology of factor VIII deficiency in hemophilia A. Hum. Mutat. 5:
1-22, 1995.
9. Antonarakis, S. E.; Rossiter, J. P.; Young, M.; Horst, J.; de Moerloose,
P.; Sommer, S. S.; Ketterling, R. P.; Kazazian, H. H., Jr.; Negrier,
C.; Vinciguerra, C.; Gitschier, J.; Goossens, M.; and 54 others
: Factor VIII inversions in severe hemophilia A: results from an international
consortium. Blood 86: 2206-2212, 1995.
10. Antonarakis, S. E.; Waber, P. G.; Kittur, S. D.; Patel, A. S.;
Kazazian, H. H., Jr.; Mellis, M. A.; Counts, R. B.; Stamatoyannopoulos,
G.; Bowie, E. J. W.; Fass, D. N.; Pittman, D. D.; Wozney, J. M.; Toole,
J. J.: Hemophilia A: detection of molecular defects and of carriers
by DNA analysis. New Eng. J. Med. 313: 842-848, 1985.
11. Antonarakis, S. E.; Youssoufian, H.; Kazazian, H. H.: Molecular
genetics of hemophilia-A in man (factor VIII deficiency). Molec.
Biol. Med. 4: 81-95, 1987.
12. Arai, M.; Higuchi, M.; Antonarakis, S. E.; Kazazian, H. H., Jr.;
Phillips, J. A., III; Janco, R. L.; Hoyer, L. W.: Characterization
of a thrombin cleavage site mutation (arg1689-to-cys) in the factor
VIII gene of two unrelated patients with cross-reacting material-positive
hemophilia A. Blood 75: 384-389, 1990.
13. Arai, M.; Inaba, H.; Higuchi, M.; Antonarakis, S. E.; Kazazian,
H. H., Jr.; Fujimaki, M.; Hoyer, L. W.: Direct characterization of
factor VIII in plasma: detection of a mutation altering a thrombin
cleavage site (arginine372-to-histidine). Proc. Nat. Acad. Sci. 86:
4277-4281, 1989.
14. Aronovich, A.; Tchorsh, D.; Katchman, H.; Eventov-Friedman, S.;
Shezen, E.; Martinowitz, U.; Blazar, B. R.; Cohen, S.; Tal, O.; Reisner,
Y.: Correction of hemophilia as a proof of concept for treatment
of monogenic diseases by fetal spleen transplantation. Proc. Nat.
Acad. Sci. 103: 19075-19080, 2006.
15. Arrants, J. E.; Jordan, P. H., Jr.; Newcomb, T. F.: Von Willebrand's
disease: a cause for massive postoperative bleeding--report of a case. Ann.
Surg. 156: 845-851, 1962.
16. Arveiler, B.; Vincent, A.; Mandel, J.-L.: Toward a physical map
of the Xq28 region in man: linking color vision, G6PD, and coagulation
factor VIII genes to an X-Y homology region. Genomics 4: 460-471,
1989.
17. Bardoni, B.; Sampietro, M.; Romano, M.; Crapanzano, M.; Mannucci,
P. M.; Camerino, G.: Characterization of a partial deletion of the
factor VIII gene in a haemophiliac with inhibitor. Hum. Genet. 79:
86-88, 1988.
18. Barker, D.; Schafer, M.; White, R.: Restriction sites containing
CpG show a higher frequency of polymorphism in human DNA. Cell 36:
131-138, 1984.
19. Barrai, I.; Cann, H. M.; Cavalli-Sforza, L. L.: Segregation analysis
of hemophilia A and B. (Letter) Am. J. Hum. Genet. 31: 226-227,
1979.
20. Barrai, I.; Cann, H. M.; Cavalli-Sforza, L. L.; de Nicola, P.
: The effect of parental age on rates of mutation for hemophilia and
evidence for differing mutation rates for hemophilia A and B. Am.
J. Hum. Genet. 20: 175-196, 1968.
21. Barrow, E. M. S.; Graham, J. B.: Factor VIII. (Letter) Lancet 301:
1312-1313, 1973. Note: Originally Volume I.
22. Baty, B. J.; Drayna, D.; Leonard, C. O.; White, R.: Prenatal
diagnosis of factor VIII deficiency to help with the management of
pregnancy and delivery. (Letter) Lancet 327: 207 only, 1986. Note:
Originally Volume I.
23. Batzer, M. A.; Deininger, P. L.; Hellmann-Blumberg, U.; Jurka,
J.; Labuda, D.; Rubin, C. M.; Schmid, C. W.; Zietkiewicz, E.; Zuckerkandl,
E.: Standardized nomenclature for Alu repeats. J. Molec. Evol. 42:
3-6, 1996.
24. Becker, J.; Schwaab, R.; Moller-Taube, A.; Schwaab, U.; Schmidt,
W.; Brackmann, H. H.; Grimm, T.; Olek, K.; Oldenburg, J.: Characterization
of the factor VIII defect in 147 patients with sporadic hemophilia
A: family studies indicate a mutation type-dependent sex ratio of
mutation frequencies. Am. J. Hum. Genet. 58: 657-670, 1996.
25. Bennett, B.; Ratnoff, O. D.: Deletion of the carrier state for
classic hemophilia. New Eng. J. Med. 7: 342-345, 1974.
26. Bennett, E.; Huehns, E. R.: Immunological differentiation of
three types of hemophilia and identification of some female carriers. Lancet 296 :
956-958, 1970. Note: Originally Volume I.
27. Berg, L.-P.; Wieland, K.; Millar, D. S.; Schlosser, M.; Wagner,
M.; Kakkar, V. V.; Reiss, J.; Cooper, D. N.: Detection of a novel
point mutation causing haemophilia A by PCR/direct sequencing of ectopically-tra nscribed
factor VIII mRNA. Hum. Genet. 85: 655-658, 1990.
28. Bernardi, F.; Marchetti, G.; Bertagnolo, V.; Faggioli, L.; Volinia,
S.; Patracchini, P.; Bartolai, S.; Vannini, F.; Felloni, L.; Rossi,
L.; Panicucci, F.; Conconi, F.: RFLP analysis in families with sporadic
hemophilia A: estimate of the mutation ratio in male and female gametes. Hum.
Genet. 76: 253-256, 1987.
29. Bernardi, F.; Volinia, S.; Patracchini, P.; Gemmati, D.; Boninsegna,
S.; Schwienbacher, C.; Marchetti, G.: A recurrent missense mutation
(arg-to-gln) and a partial deletion in factor VIII gene causing severe
haemophilia A. Brit. J. Haemat. 71: 271-276, 1989.
30. Bicocchi, M. P.; Migeon, B. R.; Pasino, M.; Lanza, T.; Bottini,
F.; Boeri, E.; Molinari, A. C.; Corsolini, F.; Morerio, C.; Acquila,
M.: Familial nonrandom inactivation linked to the X inactivation
centre in heterozygotes manifesting haemophilia A. Europ. J. Hum.
Genet. 13: 635-640, 2005.
31. Bidichandani, S. I.; Shiach, C. R.; Lanyon, W. G.; Connor, J.
M.: A novel splice donor mutation affecting position +3 in intron
6 of the factor VIII gene. Hum. Molec. Genet. 3: 651-653, 1994.
32. Biggs, R.; Rizza, C. R.: The sporadic case of haemophilia A. Lancet 308:
431-433, 1976. Note: Originally Volume II.
33. Bird, A. P.: DNA methylation and the frequency of CpG in animal
DNA. Nucleic Acids Res. 8: 1499-1504, 1980.
34. Bloom, A. L.; Peake, I. R.: Molecular genetics of factor VIII
and its disorders. Am. J. Path. 88: 319-340, 1977.
35. Bond, T. P.; Levin, W. C.; Celander, D. R.; Guest, M. M.: 'Mild
hemophilia' affecting both males and females. New Eng. J. Med. 266:
220-223, 1962.
36. Boyer, S. H.; Graham, J. B.: Linkage between the X chromosome
loci for glucose-6-phosphate dehydrogenase electrophoretic variation
and hemophilia A. Am. J. Hum. Genet. 17: 320-324, 1965.
37. Boyer, S. H.; Siggers, D. C.; Krueger, L. J.: A caveat to protein
replacement therapy for genetic disease. Immunologic implications
of accurate molecular diagnosis. Lancet 302: 654-659, 1973. Note:
Originally Volume II.
38. Briet, E.; Bakker, B.; Brocker-Vriends, A.: Somatic and germinal
mosaicism for a deletion in the factor VIII gene. (Abstract) Brit.
J. Haemat. 71 (suppl. 1): 1 only, 1989.
39. Brinke, A.; Tagliavacca, L.; Naylor, J.; Green, P.; Giangrande,
P.; Giannelli, F.: Two chimaeric transcription units result from
an inversion breaking intron 1 of the factor VIII gene and a region
reportedly affected by reciprocal translocations in T-cell leukaemia. Hum.
Molec. Genet. 5: 1945-1951, 1996.
40. Brinkhous, K. M.; Davis, P. D.; Graham, J. B.; Dodds, W. J.:
Expression and linkage of genes for X-linked hemophilia A and B in
the dog. Blood 41: 577-585, 1973.
41. Brinkhous, K. M.; Graham, J. B.: Hemophilia in the female dog. Science 111:
723-724, 1950.
42. Brocker-Vriends, A. H. J. T.; Briet, E.; Dreesen, J. C. F. M.;
Bakker, B.; Reitsma, P.; Pannekoek, H.; van de Kamp, J. J. P.; Pearson,
P. L.: Somatic origin of inherited haemophilia A. Hum. Genet. 85:
288-292, 1990.
43. Brocker-Vriends, A. H. J. T.; Rosendaal, F. R.; van Houwelingen,
J. C.; Bakker, E.; van Ommen, G. J. B.; van de Kamp, J. J. P.; Briet,
E.: Sex ratio of the mutation frequencies in haemophilia A: coagulation
assays and RFLP analysis. J. Med. Genet. 28: 672-680, 1991.
44. Casarino, L.; Pecorara, M.; Mori, P. G.; Morfini, M.; Mancuso,
G.; Scrivano, L.; Molinari, A. C.; Lanza, T.; Giavarella, G.; Loi,
A.; Perseu, L.; Cao, A.; Pirastu, M.: Molecular basis of hemophilia
A in Italians. Ric. Clin. Lab. 16: 227, 1986.
45. Casula, L.; Murru, S.; Pecorara, M.; Ristaldi, M. S.; Restagno,
G.; Mancuso, G.; Morfini, M.; De Biasi, R.; Baudo, F.; Carbonara,
A.; Mori, P. G.; Cao, A.; Pirastu, M.: Recurrent mutations and three
novel rearrangements in the factor VIII gene of hemophilia A patients
of Italian descent. Blood 75: 662-670, 1990.
46. Chan, V.; Chan, T. K.; Tong, T. M.; Todd, D.: A novel missense
mutation in exon 4 of the factor VIII:C gene resulting in moderately
severe hemophilia A. Blood 74: 2688-2691, 1989.
47. Chao, H.; Mansfield, S. G.; Bartel, R. C.; Hiriyanna, S.; Mitchell,
L. G.; Garcia-Blanco, M. A.; Walsh, C. E.: Phenotype correction of
hemophilia A mice by spliceosome-mediated RNA trans-splicing. Nature
Med. 9: 1015-1019, 2003.
48. Chediak, J.; Telfer, M. C.; Jaojaroenkul, T.; Green, D.: Lower
factor VIII coagulant activity in daughters of subjects with hemophilia
A compared to other obligate carriers. Blood 55: 552-558, 1980.
49. Coleman, R.; Genet, S. A.; Harper, J. I.; Wilkie, A. O. M.: Interaction
of incontinentia pigmenti and factor VIII mutations in a female with
biased X inactivation, resulting in haemophilia. J. Med. Genet. 30:
497-500, 1993.
50. Cone, T. E., Jr.: A case of hereditary hemorrhagic tendency (hemophilia)
reported in 1832 by a physician practicing in Simpsonville, Kentucky. Pediatrics 64:
291, 1979.
51. Cooper, D. N.; Youssoufian, H.: The CpG dinucleotide and human
genetic disease. Hum. Genet. 78: 151-155, 1988.
52. Cooper, H. A.; Wagner, R. H.: The defect in hemophilic and Von
Willebrand's disease. Plasmas studied by a recombination technique. J.
Clin. Invest. 54: 1093-1099, 1974.
53. Cutler, J. A.; Mitchell, M. J.; Smith, M. P.; Savidge, G. F.:
The identification and classification of 41 novel mutations in the
factor VIII gene (F8C). Hum. Mutat. 19: 274-278, 2002.
54. David, D.; Moreira, I.; Lalloz, M. R.; Rosa, H. A.; Schwaab, R.;
Morais, S.; Diniz, M. J.; de Deus, G.; Campos, M.; Lavinha, J.: Analysis
of the essential sequences of the factor VIII gene in twelve haemophilia
A patients by single-stranded conformation polymorphism. Blood Coagul.
Fibrinolysis 5: 257-264, 1994.
55. Denson, K. W. E.: Two forms of haemophilia? (Letter) Lancet 292:
222-223, 1968. Note: Originally Volume II.
56. Denson, K. W. E.; Biggs, R.; Haddon, M. E.; Borrett, R.; Cobb,
K.: Two types of haemophilia (A+ and A-): a study of 48 cases. Brit.
J. Haemat. 17: 163-171, 1969.
57. Diamond, C.; Kogan, S.; Levinson, B.; Gitschier, J.: Amino acid
substitutions in conserved domains of factor VIII and related proteins:
study of patients with mild and moderately severe hemophilia A. Hum.
Mutat. 1: 248-257, 1992.
58. Din, N.; Schwartz, M.; Kruse, T.; Vestertgaard, S. R.; Ahrens,
P.; Scheibel, E.; Nordfang, O.; Ezban, M.: Factor VIII gene-specific
probes used to study heritage and molecular defects in hemophilia
A. (Abstract) Ric. Clin. Lab. 16: 182 only, 1986.
59. Dombroski, B. A.; Mathias, S. L.; Nanthakumar, E.; Scott, A. F.;
Kazazian, H. H., Jr.: Isolation of an active human transposable element. Science 254:
1805-1808, 1991.
60. Dombroski, B. A.; Mathias, S. L.; Nanthakumar, E. J.; Scott, A.
F.; Kazazian, H. H., Jr.: Isolation of the L1 gene responsible for
a retrotransposition event in man. (Abstract) Am. J. Hum. Genet. 49
(suppl.): 403 only, 1991.
61. Dwarki, V. J.; Belloni, P.; Nijjar, T.; Smith, J.; Couto, L.;
Rabier, M.; Clift, S.; Berns, A.; Cohen, L. K.: Gene therapy for
hemophilia A: production of therapeutic levels of human factor VIII
in vivo in mice. Proc. Nat. Acad. Sci. 92: 1023-1027, 1995.
62. Economou, E. P.; Kazazian, H. H., Jr.; Antonarakis, S. E.: Detection
of mutations in the factor VIII gene using single-stranded conformational
polymorphism (SSCP). Genomics 13: 909-911, 1992.
63. Edgell, C.-J. S.; Kirkman, H. N.; Clemons, E.; Buchanan, P. D.;
Miller, C. H.: Prenatal diagnosis by linkage: hemophilia A and polymorphic
glucose-6-phosphate dehydrogenase. Am. J. Hum. Genet. 30: 80-84,
1978.
64. Erlich, H. A.; Gelfand, D. H.; Saiki, R. K.: Specific DNA amplification. Nat ure 331:
461-462, 1988.
65. Favier, R.; Lavergne, J.-M.; Costa, J.-M.; Caron, C.; Mazurier,
C.; Viemont, M.; Delpech, M.; Valleix, S.: Unbalanced X-chromosome
inactivation with a novel FVIII gene mutation resulting in severe
hemophilia A in a female. Blood 96: 4373-4375, 2000.
66. Fay, P. J.; Chavin, S. I.; Schroeder, D.; Young, F. E.; Marder,
V. J.: Purification and characterization of a highly purified human
factor VIII consisting of a single type of polypeptide chain. Proc.
Nat. Acad. Sci. 79: 7200-7204, 1982.
67. Feinstein, D.; Chong, M. N. Y.; Kasper, C. K.; Rapaport, S. I.
: Hemophilia A: polymorphism detectable by a factor VIII antibody. Science 163:
1071-1072, 1969.
68. Figueiredo, M. S.; Bernardi, F.; Zago, M. A.: A novel deletion
of FVIII gene associated with variable levels of FVIII inhibitor. Europ.
J. Haemat. 48: 152-154, 1992.
69. Filippi, G.; Mannucci, P. M.; Coppola, R.; Farris, A.; Rinaldi,
A.; Siniscalco, M.: Studies on hemophilia A in Sardinia bearing on
the problems of multiple allelism, carrier detection, and differential
mutation rate in the two sexes. Am. J. Hum. Genet. 36: 44-71, 1984.
70. Firshein, S. I.; Hoyer, L. W.; Lazarchick, J.; Forget, B. G.;
Hobbins, J. C.; Clyne, L. P.; Pitlick, F. A.; Muir, W. A.; Merkatz,
I. R.; Mahoney, M. J.: Prenatal diagnosis of classic hemophilia. New
Eng. J. Med. 300: 937-941, 1979.
71. Freije, D.; Schlessinger, D.: A 1.6-Mb contig of yeast artificial
chromosomes around the human factor VIII gene reveals three regions
homologous to probes for the DXS115 locus and two for the DXYS64 locus. Am.
J. Hum. Genet. 51: 66-80, 1992.
72. Frommel, D.; Muller, J. Y.; Prou-Wartelle, O.; Allain, J. P.:
Possible linkage between the major histocompatibility complex and
the immune response to factor VIII in classic haemophilia. Vox Sang. 33:
270-272, 1977.
73. Ganguly, A.; Dunbar, T.; Chen, P.; Godmilow, L.; Ganguly, T.:
Exon skipping caused by an intronic insertion of a young Alu Yb9 element
leads to severe hemophilia A. Hum. Genet. 113: 348-352, 2003.
74. Ghosh, K.; Shankarkumar, U.; Shetty, S.; Mohanty, D.: Chronic
synovitis and HLA B27 in patients with severe haemophilia. Lancet 361:
933-934, 2003.
75. Gill, P.; Ivanov, P. L.; Kimpton, C.; Piercy, R.; Benson, N.;
Tully, G.; Evett, I.; Hagelberg, E.; Sullivan, K.: Identification
of the remains of the Romanov family by DNA analysis. Nature Genet. 6:
130-135, 1994.
76. Gitschier, J.: Maternal duplication associated with gene deletion
in sporadic hemophilia. Am. J. Hum. Genet. 43: 274-279, 1988.
77. Gitschier, J.; Drayna, D.; Tuddenham, E. G. D.; White, R. L.;
Lawn, R. M.: Genetic mapping and diagnosis of haemophilia A achieved
through a BclI polymorphism in the factor VIII gene. Nature 314:
738-740, 1985.
78. Gitschier, J.; Wood, W. I.; Shuman, M. A.; Lawn, R. M.: Identification
of a missense mutation in the factor VIII gene of a mild hemophiliac. Science 23 2:
1415-1416, 1986.
79. Gitschier, J.; Wood, W. I.; Tuddenham, E. G. D.; Shuman, M. A.;
Goralka, T. M.; Chen, E. Y.; Lawn, R. M.: Detection and sequence
of mutations in the factor VIII gene of haemophiliacs. Nature 315:
427-430, 1985.
80. Graham, J. B.; Green, P. P.; McGraw, R. A.; Davis, L. M.: Application
of molecular genetics to prenatal diagnosis and carrier detection
in the hemophilias: some limitations. Blood 66: 759-764, 1985.
81. Graham, J. B.; McLendon, W. W.; Brinkhous, K. M.: Mild hemophilia:
an allelic form of the disease. Am. J. Med. Sci. 225: 46-53, 1953.
82. Gralnick, H. R.; Coller, B. S.: Molecular defects in haemophilia
A and von Willebrand's disease. Lancet 307: 837-838, 1976. Note:
Originally Volume I.
83. Green, P. M.; Bagnall, R. D.; Waseem, N. H.; Giannelli, F.: Haemophilia
A mutations in the UK: results of screening one-third of the population. Brit.
J. Haemat. 143: 115-128, 2008.
84. Green, P. M.; Montandon, A. J.; Bentley, D. R.; Giannelli, F.
: Genetics and molecular biology of haemophilias A and B. Blood Coagul.
Fibrinolysis 2: 539-565, 1991.
85. Grover, H.; Phillips, M. A.; Lillicrap, D. P.; Giles, A. R.; Garvey,
M. B.; Teitel, J.; Rivard, G.; Blanchette, V.; White, B. N.; Holden,
J. J. A.: Carrier deletion of haemophilia A using DNA markers in
families with an isolated affected male. Clin. Genet. 32: 10-19,
1987.
86. Grozdea, J.; Colombies, P.; Bierme, R.; Ducos, J.: Myeloperoxidases
and genetics of haemophilia A. (Letter) Lancet 294: 220 only, 1969.
Note: Originally Volume II.
87. Guillet, B.; Lambert, T.; d'Oiron, R.; Proulle, V.; Plantier,
J.-L.; Rafowicz, A.; Peynet, J.; Costa, J.-M.; Bendelac, L.; Laurian,
Y.; Lavergne, J.-M.: Detection of 95 novel mutations in coagulation
factor VIII gene F8 responsible for hemophilia A: results from a single
institution. Hum. Mutat. 27: 676-685, 2006.
88. Haldane, J. B. S.; Smith, C. A. B.: A new estimate of the linkage
between the genes for colour-blindness and haemophilia in man. Ann.
Eugen. 14: 10-31, 1947.
89. Harper, K.; Winter, R. M.; Pembrey, M. E.; Hartley, D.; Davies,
K. E.; Tuddenham, E. G. D.: A clinically useful DNA probe closely
linked to haemophilia A. Lancet 324: 6-8, 1984. Note: Originally
Volume II.
90. Hemker, H. C.; Muller, A. D.; Hermens, W. T.; Zwaal, R. F. A.
: Oral treatment of hemophilia A by gastrointestinal absorption of
factor VIII entrapped in liposomes. Lancet 315: 70-71, 1980. Note:
Originally Volume I.
91. Hermann, J.: Der Einfluss des Zeugungsalters auf die Mutationen
zu Haemophilie A. Humangenetik 3: 1-16, 1966.
92. Higuchi, M.; Antonarakis, S. E.; Kasch, L.; Oldenburg, J.; Economou-Petersen ,
E.; Olek, K.; Arai, M.; Inaba, H.; Kazazian, H. H., Jr.: Molecular
characterization of mild-to-moderate hemophilia A: detection of the
mutation in 25 of 29 patients by denaturing gradient gel electrophoresis. Proc.
Nat. Acad. Sci. 88: 8307-8311, 1991.
93. Higuchi, M.; Kazazian, H. H., Jr.; Kasch, L.; Warren, T. C.; McGinniss,
M. J.; Phillips, J. A., III; Kasper, C., III; Janco, R.; Antonarakis,
S. E.: Molecular characterization of severe hemophilia A suggests
that about half the mutations are not within the coding regions and
splice junctions of the factor VIII gene. Proc. Nat. Acad. Sci. 88:
7405-7409, 1991.
94. Higuchi, M.; Kochhan, L.; Olek, K.: A somatic mosaic for haemophilia
A detected at the DNA level. Molec. Biol. Med. 5: 23-27, 1988.
95. Higuchi, M.; Kochhan, L.; Schwaab, R.; Egli, H.; Brackmann, H.
H.; Horst, J.; Olek, K.: Molecular defects in hemophilia A: identification
and characterization of mutations in the factor VIII gene and family
analysis. Blood 74: 1045-1051, 1989.
96. Higuchi, M.; Wong, C.; Kochhan, L.; Olek, K.; Aronis, S.; Kasper,
C. K.; Kazazian, H. H., Jr.; Antonarakis, S. E.: Characterization
of mutations in the factor VIII gene by direct sequencing of amplified
genomic DNA. Genomics 6: 65-71, 1990.
97. Howard, P. L.; Hoag, J. B.; Bovill, E. G.; Heintz, N. H.: Spontaneous
mutation in the male gamete as a cause of hemophilia A: clarification
of a case using DNA probes. Am. J. Hemat. 28: 167-169, 1988.
98. Hoyer, L. W.: The factor VIII complex: structure and function. Blood 58:
1-13, 1981.
99. Hoyer, L. W.; Breckenridge, R. T.: Two forms of haemophilia?
(Letter) Lancet 292: 457 only, 1968. Note: Originally Volume II.
100. Inaba, H.; Fujimaki, M.; Kazazian, H. H., Jr.; Antonarakis, S.
E.: Mild hemophilia A resulting from arg-to-leu substitution in exon
26 of the factor VIII gene. Hum. Genet. 81: 335-338, 1989.
101. Inaba, H.; Fujimaki, M.; Kazazian, H. H., Jr.; Antonarakis, S.
E.: MspI polymorphic site in intron 22 of the factor VIII gene in
the Japanese population. Hum. Genet. 84: 214-215, 1990.
102. Ivanov, P. L.; Wadhams, M. J.; Roby, R. K.; Holland, M. M.; Weedn,
V. W.; Parsons, T. J.: Mitochondrial DNA sequence heteroplasmy in
the Grand Duke of Russia Georgij Romanov establishes the authenticity
of the remains of Tsar Nicholas II. Nature Genet. 12: 417-420, 1996.
103. Jaffe, E. A.; Nachman, R. L.: Subunit structure of factor VIII
antigen synthesized by cultured human endothelial cells. J. Clin.
Invest. 56: 698-702, 1975.
104. James, P. D.; Raut, S.; Rivard, G. E.; Poon, M.-C.; Warner, M.;
McKenna, S.; Leggo, J.; Lillicrap, D.: Aminoglycoside suppression
of nonsense mutations in severe hemophilia. Blood 106: 3043-3048,
2005.
105. Janco, R. L.; Phillips, J. A., III; Orlando, P. J.; Woodard,
M. J.; Wion, K. L.; Lawn, R. M.: Detection of hemophilia A carriers
using intragenic factor VIII:C DNA polymorphisms. Blood 69: 1539-1541,
1987.
106. Johnson, D. J.; Pemberton, S.; Acquila, M.; Mori, P. G.; Tuddenham,
E. G.; O'Brien, D. P.: Factor VIII S373L: mutation at P1' site confers
thrombin cleavage resistance, causing mild haemophilia A. Thromb.
Haemost. 71: 428-433, 1994.
107. Jonsdottir, S.; Diamond, C.; Levinson, B.; Magnusson, S.; Jensson,
O.; Gitschier, J.: Missense mutations causing mild hemophilia A in
Iceland detected by denaturing gradient gel electrophoresis. Hum.
Mutat. 1: 506-508, 1992.
108. Kay, M. A.; High, K.: Gene therapy for the hemophilias. (Commentary) Proc.
Nat. Acad. Sci. 96: 9973-9975, 1999.
109. Kazazian, H. H., Jr.; Wong, C.; Youssoufian, H.; Scott, A. F.;
Phillips, D. G.; Antonarakis, S. E.: Haemophilia A resulting from
de novo insertion of L1 sequences represents a novel mechanism for
mutation in man. Nature 332: 164-166, 1988.
110. Kemball-Cook, G.; Tuddenham, E. G. D.: The factor VIII mutation
database on the World Wide Web: the haemophilia A mutation, search,
test and resource site. HAMSTeRS update (version 3.0). Nucleic Acids
Res. 25: 128-132, 1997.
111. Kenwrick, S.; Gitschier, J.: A contiguous, 3-Mb physical map
of Xq28 extending from the colorblindness locus to DXS15. Am. J.
Hum. Genet. 45: 873-882, 1989.
112. Kenwrick, S.; Levinson, B.; Taylor, S.; Shapiro, A.; Gitschier,
J.: Isolation and sequence of two genes associated with a CpG island
5-prime of the factor VIII gene. Hum. Molec. Genet. 1: 179-186,
1992.
113. Kitchens, C. S.: Occult hemophilia. Johns Hopkins Med. J. 146:
255-259, 1980.
114. Klein, H. G.; Aledort, L. M.; Bouma, B. N.; Hoyer, L. W.; Zimmerman,
T. S.; De Mets, D. L.: A co-operative study for the detection of
the carrier state of classic hemophilia. New Eng. J. Med. 296: 959-962,
1977.
115. Kogan, S.; Gitschier, J.: Mutations and a polymorphism in the
factor VIII gene discovered by denaturing gradient gel electrophoresis. Proc.
Nat. Acad. Sci. 87: 2092-2096, 1990.
116. Kogan, S. C.; Doherty, M.; Gitschier, J.: An improved method
for prenatal diagnosis of genetic diseases by analysis of amplified
DNA sequences: application to hemophilia A. New Eng. J. Med. 317:
985-990, 1987.
117. Krepelova, A.; Varlova, Z.; Zavadil, J.; Brdicka, R.: Factor
VIII gene deletions in haemophilia A patients in Czechoslovakia. Brit.
J. Haemat. 86: 271-276, 1992.
118. Lacroix-Desmazes, S.; Bayry, J.; Misra, N.; Horn, M. P.; Villard,
S.; Pashov, A.; Stieltjes, N.; d'Oiron, R.; Saint-Remy, J.-M.; Hoebeke,
J.; Kazatchkine, M. D.; Kaveri, S. V.: The prevalence of proteolytic
antibodies against factor VIII in hemophilia A. New Eng. J. Med. 346:
662-667, 2002.
119. Lakich, D.; Kazazian, H. H., Jr.; Antonarakis, S. E.; Gitschier,
J.: Inversions disrupting the factor VIII gene are a common cause
of severe haemophilia A. Nature Genet. 5: 236-241, 1993.
120. Lavergne, J. M.; Bahnak, B. R.; Vidaud, M.; Laurian, Y.; Meyer,
D.: A directed search for mutations in hemophilia A using restriction
enzyme analysis and denaturing gradient gel electrophoresis: a study
of seven exons in the factor VIII gene of 170 cases. Nouv. Rev. Fr.
Hematol. 34: 85-91, 1992.
121. Lavery, S.: Preimplantation genetic diagnosis of haemophilia. Brit.
J. Haemat. 144: 303-307, 2008.
122. Lawn, R. M.: The molecular genetics of hemophilia: blood clotting
factors VIII and IX. Cell 42: 405-406, 1985.
123. Leuer, M.; Oldenburg, J.; Lavergne, J.-M.; Ludwig, M.; Fregin,
A.; Eigel, A.; Ljung, R.; Goodeve, A.; Peake, I.; Olek, K.: Somatic
mosaicism in hemophilia A: a fairly common event. Am. J. Hum. Genet. 69:
75-87, 2001.
124. Levin, J.: Personal Communication. Baltimore, Md. 12/1979.
125. Levinson, B.; Janco, R.; Phillips, J., III; Gitschier, J.: A
novel missense mutation in the factor VIII gene identified by analysis
of amplified hemophilia DNA sequences. Nucleic Acids Res. 15: 9797-9805,
1987.
126. Levinson, B.; Kenwrick, S.; Lakich, D.; Hammonds, G.; Gitschier,
J.: A transcribed gene in an intron of the human factor VIII gene. Genomics 7:
1-11, 1990.
127. Levinson, B.; Lehesjoki, A.-E.; de la Chapelle, A.; Gitschier,
J.: Molecular analysis of hemophilia A mutations in the Finnish population. Am.
J. Hum. Genet. 46: 53-62, 1990.
128. Lewis, J. H.; Bontempo, F. A.; Spero, J. A.; Ragni, M. V.; Starzl,
T. E.: Liver transplantation in a hemophiliac. New Eng. J. Med. 312:
1189-1190, 1985.
129. Lillicrap, D. P.; Taylor, S. A. M.; Grover, H.; Teitel, J.; Giles,
A. R.; Holden, J. J. A.; White, B. N.: Genetic analysis in hemophilia
A: identification of a large F.VIII gene deletion in a patient with
high titre antibodies to human and porcine F.VIII. (Abstract) Blood 68:
337a only, 1986.
130. Lin, S.-W.; Lin, S.-R.; Shen, M.-C.: Characterization of genetic
defects of hemophilia A in patients of Chinese origin. Genomics 18:
496-504, 1993.
131. Lozier, J. N.; Dutra, A.; Pak, E.; Zhou, N.; Zheng, Z.; Nichols,
T. C.; Bellinger, D. A.; Read, M.; Morgan, R. A.: The Chapel Hill
hemophilia A dog colony exhibits a factor VIII gene inversion. Proc.
Nat. Acad. Sci. 99: 12991-12996, 2002.
132. Mannucci, P. M.; Tuddenham, E. G. D.: The hemophilias--from
royal genes to gene therapy. New Eng. J. Med. 344: 1773-1779, 2001.
133. Marchesi, S. L.; Shulman, N. R.; Gralnick, H. R.: Studies on
the purification and characterization of human factor VIII. J. Clin.
Invest. 51: 2151-2161, 1972.
134. Mazurier, C.; Parquet-Gernez, A.; Gaucher, C.; Lavergne, J.-M.;
Goudemand, J.: Factor VIII deficiency not induced by FVIII gene mutation
in a female first cousin of two brothers with haemophilia A. Brit.
J. Haemat. 119: 390-392, 2002.
135. McGinniss, M. J.; Kazazian, H. H., Jr.; Hoyer, L. W.; Bi, L.;
Inaba, H.; Antonarakis, S. E.: Spectrum of mutations in CRM-positive
and CRM-reduced hemophilia A. Genomics 15: 392-398, 1993.
136. McKusick, V. A.: The royal hemophilia. Sci. Am. 213(2): 88-95,
1965.
137. McKusick, V. A.: The earliest record of hemophilia in America? Blood 19:
243-244, 1962.
138. McKusick, V. A.: Hemophilia in early New England: a follow-up
of four kindreds in which hemophilia occurred in pre-Revolutionary
period. J. Hist. Med. 17: 342-365, 1962.
139. McKusick, V. A.: On the X Chromosome of Man. Washington, D.
C.: Am. Inst. Biol. Sci. (pub.) 1964.
140. Mibashan, R. S.; Peake, I. R.; Rodeck, C. H.; Thumpston, J. K.;
Furlong, R. A.; Gorer, R.; Bains, L.; Bloom, A. L.: Dual diagnosis
of prenatal haemophilia A by measurement of fetal factor VIIIC and
VIIIC antigen (VIIICAg). Lancet 316: 994-997, 1980. Note: Originally
Volume II.
141. Migeon, B. R.; Axelman, J.; Jan de Beur, S.; Valle, D.; Mitchell,
G. A.; Rosenbaum, K. N.: Selection against lethal alleles in females
heterozygous for incontinentia pigmenti. Am. J. Hum. Genet. 44:
100-106, 1989.
142. Migeon, B. R.; McGinniss, M. J.; Antonarakis, S. E.; Axelman,
J.; Stasiowski, B. A.; Youssoufian, H.; Kearns, W. G.; Chung, A.;
Pearson, P. L.; Kazazian, H. H., Jr.; Muneer, R. S.: Severe hemophilia
A in a female by cryptic translocation: order and orientation of factor
VIII within Xq28. Genomics 16: 20-25, 1993.
143. Mikami, S.: Gene analysis in haemophilia A--restriction fragment
length polymorphism and molecular defects in the factor VIII gene. Acta
Haemat. Jpn. 51: 1680-1688, 1988.
144. Millar, D. S.; Steinbrecher, R. A.; Wieland, K.; Grundy, C. B.;
Martinowitz, U.; Krawczak, M.; Zoll, B.; Whitmore, D.; Stephenson,
J.; Mibashan, R. S.; Kakkar, V. V.; Cooper, D. N.: The molecular
genetic analysis of haemophilia A: characterization of six partial
deletions in the factor VIII gene. Hum. Genet. 86: 219-227, 1990.
145. Millar, D. S.; Steinbrecher, R. A.; Wieland, K.; Grundy, C. B.;
Martinowitz, U.; Krawczak, M.; Zoll, B.; Whitmore, D.; Stephenson,
J.; Mibashan, R. S.; Kakkar, V. V.; Cooper, D. N.: The molecular
genetic analysis of haemophilia A; characterization of six partial
deletions in the factor VIII gene. Hum. Genet. 86: 219-227, 1990.
146. Millar, D. S.; Zoll, B.; Martinowitz, U.; Kakkar, V. V.; Cooper,
D. N.: The molecular genetics of haemophilia A: screening for point
mutations in the factor VIII gene using the restriction enzyme TaqI. Hum.
Genet. 87: 607-612, 1991.
147. Mori, P. G.; Pasino, M.; Vadala, C. R.; Bisogni, M. C.; Tonini,
G. P.; Scarabicchi, S.: Haemophilia 'A' in a 46,X,i(Xq) female. Brit.
J. Haemat. 43: 143-147, 1979.
148. Muneer, R. S.; Coffman, M. A.; Thompson, L. M.; Sexauer, C. L.;
Rennert, O. M.: Classic hemophilia in a female with X/17 complex
translocation and partial deletion of the long arm X chromosome (Xq11-13). Am.
J. Hum. Genet. 39: A126, 1986.
149. Murru, S.; Casula, L.; Pecorara, M.; Mori, P.; Cao, A.; Pirastu,
M.: Illegitimate recombination produced a duplication within the
FVIII gene in a patient with mild hemophilia A. Genomics 7: 115-118,
1990.
150. Myers, R. M.; Fischer, S. G.; Lerman, L. S.; Maniatis, T.: Nearly
all single base substitutions in DNA fragments joined to a GC-clamp
can be detected by denaturing gradient gel electrophoresis. Nucleic
Acids Res. 13: 3131-3145, 1985.
151. Myers, R. M.; Fischer, S. G.; Maniatis, T.; Lerman, L. S.: Modification
of the melting properties of duplex DNA by attachment of a GC-rich
DNA sequence as determined by denaturing gradient gel electrophoresis. Nucleic
Acids Res. 13: 3111-3129, 1985.
152. Nafa, K.; Bundis, M.; Deburgrave, N.; Bardin, J.-M.; Sultan,
Y.; Kaplan, J.-C.; Delpech, M.: A novel mutation (Arg-to-Leu in exon
18) in factor VIII gene responsible for moderate hemophilia A. Hum.
Mutat. 1: 77-78, 1992.
153. Nafa, K.; Meriane, F.; Reghis, A.; Benabadji, M.; Demenais, F.;
Guilloud-Bataille, M.; Sultan, Y.; Kaplan, J. C.; Delpech, M.: Investigation
of factor VIIIC gene restriction fragment length polymorphisms and
search for deletions in hemophiliac subjects in Algeria. Hum. Genet. 84:
401-405, 1990.
154. Naylor, J.; Brinke, A.; Hassock, S.; Green, P. M.; Giannelli,
F.: Characteristic mRNA abnormality found in half the patients with
severe haemophilia A is due to large DNA inversions. Hum. Molec.
Genet. 2: 1773-1778, 1993.
155. Naylor, J. A.; Green, P. M.; Montandon, A. J.; Rizza, C. R.;
Giannelli, F.: Detection of three novel mutations in two haemophilia
A patients by rapid screening of whole essential region of factor
VIII gene. Lancet 337: 635-639, 1991.
156. Naylor, J. A.; Green, P. M.; Rizza, C. R.; Giannelli, F.: Factor
VIII gene explains all cases of haemophilia A. Lancet 340: 1066-1067,
1992.
157. Naylor, J. A.; Green, P. M.; Rizza, C. R.; Giannelli, F.: Analysis
of factor VIII mRNA reveals defects in everyone of 28 haemophilia
A patients. Hum. Molec. Genet. 2: 11-17, 1993.
158. Nilsson, I. M.; Berntorp, E.; Zettervall, O.: Induction of immune
tolerance in patients with hemophilia and antibodies to factor VIII
by combined treatment with intravenous IgG, cyclophosphamide, and
factor VIII. New Eng. J. Med. 318: 947-950, 1988.
159. Nilsson, I. M.; Blomback, M.; Ramgren, O.: Investigations on
hemophilia A and B carriers. Bibl. Haemat. 26: 26-29, 1966.
160. Nilsson, I. M.; Blomback, M.; Ramgren, O.; Von Francken, I.:
Haemophilia in Sweden. II. Carriers of haemophilia A and B. Acta
Med. Scand. 171: 223-235, 1962.
161. Nilsson, I. M.; Blomback, M.; Von Francken, I.: On an inherited
autosomal hemorrhagic diathesis with antihemophilic globulin (AHG)
deficiency and prolonged bleeding time. Acta Med. Scand. 159: 35-57,
1957.
162. Nilsson, I. M.; Lamme, S.: On acquired hemophilia A: a survey
of 11 cases. Acta Med. Scand. 208: 5-12, 1980.
163. Nisen, P. D.; Waber, P. G.: Nonrandom X chromosome DNA methylation
patterns in hemophiliac females. J. Clin. Invest. 83: 1400-1403,
1989.
164. Norman, J. C.; Covelli, V. H.; Sise, H. S.: Transplantation
of the spleen. (Editorial) Ann. Intern. Med. 78: 700-704, 1968.
165. O'Brien, D. P.; Pattinson, J. K.; Tuddenham, E. G. D.: Purification
and characterization of factor VIII 372-cys: a hypofunctional cofactor
from a patient with moderately severe hemophilia A. Blood 75: 1664-1672,
1990.
166. Oberle, I.; Camerino, G.; Heilig, R.; Grunebaum, L.; Cazenave,
J.-P.; Crapanzano, C.; Mannucci, P. M.; Mandel, J.-L.: Genetic screening
for hemophilia A (classic hemophilia) with a polymorphic DNA probe. New
Eng. J. Med. 312: 682-686, 1985.
167. Oberle, I.; Drayna, D.; Camerino, G.; White, R.; Mandel, J.-L.
: The telomeric region of the human X chromosome long arm: presence
of a highly polymorphic DNA marker and analysis of recombination frequency. Proc .
Nat. Acad. Sci. 82: 2824-2828, 1985.
168. Oldenburg, J.; Rost, S.; El-Maarri, O.; Leuer, M.; Olek, K.;
Muller, C. R.; Schwaab, R.: De novo factor VIII gene intron 22 inversion
in a female carrier presents as a somatic mosaicism. Blood 96: 2905-2906,
2000.
169. Pasi, K. J.: Gene therapy for haemophilia. Brit. J. Haemat. 115:
744-757, 2001.
170. Patterson, M.; Gitschier, J.; Bloomfield, J.; Bell, M.; Dorkins,
H.; Froster-Iskenius, U.; Sommer, S.; Sobell, J.; Schaid, D.; Thibodeau,
S.; Davies, K. E.: An intronic region within the human factor VIII
gene is duplicated within Xq28 and is homologous to the polymorphic
locus DXS115 (767). Am. J. Hum. Genet. 44: 679-685, 1989.
171. Patterson, M.; Schwartz, C.; Bell, M.; Sauer, S.; Hofker, M.;
Trask, B.; van den Engh, G.; Davies, K. E.: Physical mapping studies
on the human X chromosome in the region Xq27-Xqter. Genomics 1:
297-306, 1987.
172. Pattinson, J. K.; Millar, D. S.; McVey, J. H.; Grundy, C. B.;
Wieland, K.; Mibashan, R. S.; Martinowitz, U.; Tan-Un, K.; Vidaud,
M.; Goossens, M.; Sampietro, M.; Mannucci, P. M.; and 17 others
: The molecular genetic analysis of hemophilia A: a directed search
strategy for the detection of point mutations in the human factor
VIII gene. Blood 76: 2242-2248, 1990.
173. Paynton, C.; Sarkar, G.; Sommer, S. S.: Identification of mutations
in two families with sporadic hemophilia A. Hum. Genet. 87: 397-400,
1991.
174. Peake, I. R.; Lillicrap, D. P.; Liddell, M. B.; Matthews, R.
J.; Bloom, A. L.: Linked and intragenic probes for haemophilia A. Lancet 326:
1003-1004, 1985. Note: Originally Volume II.
175. Pecorara, M.; Casarino, L.; Mori, P. G.; Morfini, M.; Mancuso,
G.; Scrivano, A. M.; Boeri, E.; Molinari, A. C.; De Biasi, R.; Ciavarella,
N.; Bencivelli, F.; Repa, T.; Barbujani, G.; Loi, A.; Perseu, L.;
Cao, A.; Pirastu, M.: Hemophilia A: carrier detection and prenatal
diagnosis by DNA analysis. Blood 70: 531-535, 1987.
176. Pieneman, W. C.; Reitsma, P. H.; Briet, E.: Double strand conformation
polymorphism (DSCP) detects two point mutations at codon 280 (AAC-ATC)
and at codon 431 (TAC-AAC) of the blood coagulation factor VIII gene. Thromb.
Haemost. 69: 473-475, 1993.
177. Pignone, A.; Matucci-Cerinic, M.; Morfini, M.; Lombardi, A.;
Rossi Ferrini, P. L.; Cagnoni, M.: Suppression of autoantibodies
to factor VIII and correction of factor VIII deficiency with a combined
steroid-cyclophosphamide-porcine factor VIII treatment in a patient
with rheumatoid arthritis. J. Intern. Med. 231: 617-619, 1992.
178. Plug, I.; Mauser-Bunschoten, E. P.; Brocker-Vriends, A. H. J.
T.; van Amstel, H. K. P.; van der Bom, J. G.; van Diemen-Homan, J.
E. M.; Willemse, J.; Rosendaal, F. R.: Bleeding in carriers of hemophilia. Blood 108:
52-56, 2006.
179. Pola, V.; Svojitka, J.: Klassische Haemophilie bei Frauen. Folia
Haemat. 75: 43-51, 1957.
180. Poustka, A.; Dietrich, A.; Langenstein, G.; Toniolo, D.; Warren,
S. T.; Lehrach, H.: Physical map of human Xq27-qter: localizing the
region of the fragile X mutation. Proc. Nat. Acad. Sci. 88: 8302-8306,
1991.
181. Pratt, K. P.; Shen, B. W.; Takeshima, K.; Davie, E. W.; Fujikawa,
K.; Stoddard, B. L.: Structure of the C2 domain of human factor VIII
at 1.5 angstrom resolution. Nature 402: 439-442, 1999.
182. Rapaport, S. I.; Patch, M. J.; Moore, F. J.: Anti-hemophilic
globulin levels in carriers of hemophilia A. J. Clin. Invest. 39:
1619-1625, 1960.
183. Ratnoff, O. D.: Antihemophilic factor (factor VIII). Ann. Intern.
Med. 88: 403-409, 1978.
184. Ratnoff, O. D.; Bennett, B.: The genetics of hereditary disorders
of blood coagulation. Science 179: 1291-1298, 1973.
185. Ratnoff, O. D.; Lewis, J. H.: Heckathorn's disease: variable
functional deficiency of antihemophilic factor (factor VIII). Blood 46:
161-173, 1975.
186. Reiner, A. P.; Stray, S. M.; Thompson, A. R.: Three missense
mutations in Arg codons of the factor VIII gene of mild to moderately
severe hemophilia A patients. Thromb. Res. 66: 93-99, 1992.
187. Reiner, A. P.; Thompson, A. R.: Screening for nonsense mutations
in patients with severe hemophilia A can provide rapid, direct carrier
detection. Hum. Genet. 89: 88-94, 1992.
188. Renault, N. K.; Dyack, S.; Dobson, M. J.; Costa, T.; Lam, W.
L.; Greer, W. L.: Heritable skewed X-chromosome inactivation leads
to haemophilia A expression in heterozygous females. Europ. J. Hum.
Genet. 15: 628-637, 2007.
189. Richardson, D. W.; Robinson, A. G.: Desmopressin. Ann. Intern.
Med. 103: 228-239, 1985.
190. Roberts, D. F.: The genetic basis of variation in factor VIII
levels among haemophiliacs. J. Med. Genet. 8: 136-139, 1971.
191. Robertson, J. H.; Trueman, R. G.: Combined hemophilia and Christmas
disease. Blood 24: 281-288, 1964.
192. Rosendaal, F. R.; Briet, E.; Stibbe, J.; van Herpen, G.; Gevers
Leuven, J. A.; Hofman, A.; Vandenbroucke, J. P.: Haemophilia protects
against ischaemic heart disease: a study of risk factors. Brit. J.
Haemat. 75: 525-530, 1990.
193. Rosendaal, F. R.; Brocker-Vriends, A. H. J. T.; van Houwelingen,
J. C.; Smit, C.; Varekamp, I.; van Dijck, H.; Suurmeijer, T. P. B.
M.; Vandenbroucke, J. P.; Briet, E.: Sex ratio of the mutation frequencies
in haemophilia A: estimation and meta-analysis. Hum. Genet. 86:
139-146, 1990.
194. Rossiter, J. P.; Young, M.; Kimberland, M. L.; Hutter, P.; Ketterling,
R. P.; Gitschier, J.; Horst, J.; Morris, M. A.; Schaid, D. J.; de
Moerloose, P.; Sommer, S. S.; Kazazian, H. H., Jr.; Antonarakis, S.
E.: Factor VIII gene inversions causing severe hemophilia A originate
almost exclusively in male germ cells. Hum. Molec. Genet. 3: 1035-1039,
1994.
195. Roth, D. A.; Tawa, N. E., Jr.; O'Brien, J. M.; Treco, D. A.;
Selden, R. F.: Nonviral transfer of the gene encoding coagulation
factor VIII in patients with severe hemophilia A. New Eng. J. Med. 344:
1735-1742, 2001.
196. Saiki, R. K.; Scharf, S.; Faloona, F.; Mullis, K. B.; Horn, G.
T.; Erlich, H. A.; Arnheim, N.: Enzymatic amplification of beta-globin
genomic sequences and restriction site analysis for diagnosis of sickle
cell anemia. Science 230: 1350-1354, 1985.
197. Samama, M.; Perrotez, C.; Houissa, R.; Hafsia, A.; Seger, J.
: Hemophilic A feminine avec deletion d'une partie du bras long d'un
chromosome X. Path. Biol. (Paris) 25 (suppl.): 10-17, 1977.
198. Santacroce, R.; Acquila, M.; Belvini, D.; Castaldo, G.; Garagiola,
I.; Giacomelli, S. H.; Lombardi, A. M.; Minuti, B.; Riccardi, F.;
Salviato, R.; Tagliabue, L.; Grandone, E.; Margaglione, M.; the AICE-Genetics
Study Group: Identification of 217 unreported mutations in the F8
gene in a group of 1,410 unselected Italian patients with hemophilia
A. J. Hum. Genet. 53: 275-284, 2008.
199. Schiffman, S.; Rapaport, S. I.: Increased factor VIII levels
in suspected carriers of hemophilia A: taking contraceptives by mouth. New
Eng. J. Med. 275: 599, 1966.
200. Schwaab, R.; Brackmann, H.-H.; Meyer, C.; Seehafer, J.; Kirchgesser,
M.; Haack, A.; Olek, K.; Tuddenham, E. G. D.; Oldenburg, J.: Haemophilia
A: mutation type determines risk of inhibitor formation. Thromb.
Haemat. 74: 1402-1406, 1995.
201. Schwaab, R.; Oldenburg, J.; Tuddenham, E. G. D.; Brackmann, H.
H.; Olek, K.: Mutations in haemophilia A. Brit. J. Haemat. 83:
450-458, 1993.
202. Schwartz, R. S.; Abildgaard, C. F.; Aledort, L. M.; Arkin, S.;
Bloom, A. L.; Brackmann, H. H.; Brettler, D. B.; Fukui, H.; Hilgartner,
M. W.; Inwood, M. J.; Kasper, C. K.; Kernoff, P. B. A.; Levine, P.
H.; Lusher, J. M.; Mannucci, P. M.; Scharrer, I.; MacKenzie, M. A.;
Pancham, N.; Kuo, H. S.; Allred, R. U.; the Recombinant Factor VIII
Study Group: Human recombinant DNA-derived antihemophilic factor
(factor VIII) in the treatment of hemophilia A. New Eng. J. Med. 323:
1800-1805, 1990.
203. Seligsohn, U.; Zivelin, A.; Perez, C.; Modan, M. A.: Detection
of hemophilia A carriers by replicate factor VIII activity and factor
VIII antigenicity determinations. Brit. J. Haemat. 42: 433-439,
1979.
204. Shima, M.; Ware, J.; Yoshioka, A.; Fukui, H.; Fulcher, C. A.
: An arginine to cysteine amino acid substitution at a critical thrombin
cleavage site in a dysfunctional factor VIII molecule. Blood 74:
1612-1617, 1989.
205. Sie, P.; Caranobe, C.; Benalioua, M.; Boneu, B.: Homozygous
hemophilia A in a female. (Letter) Thromb. Haemost. 54: 728 only,
1985.
206. Smith, C. A. B.: Personal Communication. London 1968.
207. Soucie, J. M.; Evatt, B.; Jackson, D.; Hemophilia Surveillance
System Project Investigators: Occurrence of hemophilia in the United
States. Am. J. Hemat. 59: 288-294, 1998.
208. Sramek, A.; Kriek, M.; Rosendaal, F. R.: Decreased mortality
of ischaemic heart disease among carriers of haemophilia. Lancet 362:
351-354, 2003.
209. Stevens, R. F.: The history of haemophilia in the royal families
of Europe. Brit. J. Haemat. 105: 25-32, 1999.
210. Stites, D. P.; Hershgold, E. J.; Perlman, J. D.; Fudenberg, H.
H.: Factor VIII detection by hemagglutination inhibition: hemophilia
A and von Willebrand's disease. Science 171: 196-197, 1971.
211. Stoneking, M.; Melton, T.; Nott, J.; Barritt, S.; Roby, R.; Holland,
M.; Weedn, V.; Gill, P.; Kimpton, C.; Aliston-Greiner, R.; Sullivan,
K.: Establishing the identity of Anna Anderson Manahan. (Letter) Nature
Genet. 9: 9-10, 1995.
212. Sukarova, E.; Dimovski, A. J.; Tchacarova, P.; Petkov, G. H.;
Efremov, G. D.: An Alu insert as the cause of a severe form of hemophilia
A. Acta Haemat. 106: 126-129, 2001.
213. Tantravahi, U.; Murty, V. V. V. S.; Jhanwar, S. C.; Toole, J.
J.; Woozney, J. M.; Chaganti, R. S. K.; Latt, S. A.: Physical mapping
of the factor VIII gene proximal to two polymorphic DNA probes in
human chromosome band Xq28: implications for factor VIII gene segregation
analysis. Cytogenet. Cell Genet. 42: 75-79, 1986.
214. Toole, J. J.; Knopf, J. L.; Wozney, J. M.; Sultzman, L. A.; Buecker,
J. L.; Pittman, D. D.; Kaufman, R. J.; Brown, E.; Shoemaker, C.; Orr,
E. C.; Amphlett, G. W.; Foster, W. B.; Coe, M. L.; Knutson, G. J.;
Fass, D. N.; Hewick, R. M.: Molecular cloning of a cDNA encoding
human antihaemophilic factor. Nature 312: 342-347, 1984.
215. Traystman, M. D.; Higuchi, M.; Kasper, C. K.; Antonarakis, S.
E.; Kazazian, H. H., Jr.: Use of denaturing gradient gel electrophoresis
to detect point mutations in the factor VIII gene. Genomics 6: 293-301,
1990.
216. Tuddenham, E. G. D.; Lazarchick, J.; Hoyer, L. W.: Synthesis
and release of factor VIII by cultured human endothelial cells. Brit.
J. Haemat. 47: 617-626, 1981.
217. Valleix, S.; Vinciguerra, C.; Lavergne, J.-M.; Leuer, M.; Delpech,
M.; Negrier, C.: Skewed X-chromosome inactivation in monochorionic
diamniotic twin sisters results in severe and mild hemophilia A. Blood 100:
3034-3036, 2002.
218. VandenDriessche, T.; Vanslembrouck, V.; Goovaerts, I.; Zwinnen,
H.; Vanderhaeghen, M.-L.; Collen, D.; Chuah, M. K. L.: Long-term
expression of human coagulation factor VIII and correction of hemophilia
A after in vivo retroviral gene transfer in factor VIII-deficient
mice. Proc. Nat. Acad. Sci. 96: 10379-10384, 1999.
219. Vidaud, D.; Vidaud, M.; Plassa, F.; Gazengel, C.; Noel, B.; Goossens,
M.: Father-to-son transmission of hemophilia A due to uniparental
disomy. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A226 only, 1989.
220. Viel, K. R.; Ameri, A.; Abshire, T. C.; Iyer, R. V.; Watts, R.
G.; Lutcher, C.; Channell, C.; Cole, S. A.; Fernstrom, K. M.; Nakaya,
S.; Kasper, C. K.; Thompson, A. R.; Almasy, L.; Howard, T. E.: Inhibitors
of factor VIII in black patients with hemophilia. New Eng. J. Med. 360:
1618-1627, 2009.
221. Vogel, F.: A probable sex difference in some mutation rates. Am.
J. Hum. Genet. 29: 312-319, 1977.
222. Wacey, A. I.; Kemball-Cook, G.; Kazazian, H. H.; Antonarakis,
S. E.; Schwaab, R.; Lindley, P.; Tuddenham, E. G. D.: The haemophilia
A mutation search test and resource site, home page of the factor
VIII mutation database: HAMSTeRS. Nucleic Acids Res. 24: 100-102,
1996.
223. Wehnert, M.; Herrmann, F. H.; Wulff, K.: Partial deletions of
factor VIII gene as molecular diagnostic markers in hemophilia A. Dis.
Markers 7: 113-117, 1989.
224. Windsor, S.; Lyng, A.; Taylor, S. A. M.; Ewenstein, B. M.; Neufeld,
E. J.; Lillicrap, D.: Severe haemophilia A in a female resulting
from two de novo factor VIII mutations. Brit. J. Haemat. 90: 906-909,
1995.
225. Winter, R. M.; Tuddenham, E. G. D.; Goldman, E.; Matthews, K.
B.: A maximum likelihood estimate of the sex ratio of mutation rates
in haemophilia A. Hum. Genet. 64: 156-159, 1983.
226. Wood, W. I.; Capon, D. J.; Simonsen, C. C.; Eaton, D. L.; Gitschier,
J.; Keyt, B.; Seeburg, P. H.; Smith, D. H.; Hollingshead, P.; Wion,
K. L.; Delwart, E.; Tuddenham, E. G. D.; Vehar, G. A.; Lawn, R. M.
: Expression of active human factor VIII from recombinant DNA clones. Nature 312 :
330-337, 1984.
227. Woodliff, H. J.; Jackson, J. M.: Combined haemophilia and Christmas
disease: a genetic study of a patient and his relatives. Med. J.
Aust. 53: 658-661, 1966.
228. Woods-Samuels, P.; Wong, C.; Mathias, S. L.; Scott, A. F.; Kazazian,
H. H., Jr.; Antonarakis, S. E.: Characterization of a nondeleterious
L1 insertion in an intron of the human factor VIII gene and further
evidence of open reading frames in functional L1 elements. Genomics 4:
290-296, 1989.
229. Woolf, L. I.: Gene expression in heterozygotes. Nature 194:
609-610, 1962.
230. Young, M.; Inaba, H.; Hoyer, L. W.; Higuchi, M.; Kazazian, H.
H., Jr.; Antonarakis, S. E.: Partial correction of a severe molecular
defect in hemophilia A, because of errors during expression of the
factor VIII gene. Am. J. Hum. Genet. 60: 565-573, 1997.
231. Youssoufian, H.; Antonarakis, S. E.; Aronis, S.; Tsiftis, G.;
Phillips, D. G.; Kazazian, H. H., Jr.: Characterization of five partial
deletions of the factor VIII gene. Proc. Nat. Acad. Sci. 84: 3772-3776,
1987.
232. Youssoufian, H.; Antonarakis, S. E.; Bell, W.; Griffin, A. M.;
Kazazian, H. H., Jr.: Nonsense and missense mutations in hemophilia
A: estimate of the relative mutation rate at CG dinucleotides. Am.
J. Hum. Genet. 42: 718-725, 1988.
233. Youssoufian, H.; Antonarakis, S. E.; Kasper, C. K.; Phillips,
D. G.; Kazazian, H. H., Jr.: The spectrum and origin of mutations
in hemophilia A. (Abstract) Am. J. Hum. Genet. 41: A249 only, 1987.
234. Youssoufian, H.; Kasper, C. K.; Phillips, D. G.; Kazazian, H.
H., Jr.; Antonarakis, S. E.: Restriction endonuclease mapping of
six novel deletions of the factor VIII gene in hemophilia A. Hum.
Genet. 80: 143-148, 1988.
235. Youssoufian, H.; Kazazian, H. H., Jr.; Phillips, D. G.; Aronis,
S.; Tsiftis, G.; Brown, V. A.; Antonarakis, S. E.: Recurrent mutations
in haemophilia A give evidence for CpG mutation hotspots. Nature 324:
380-382, 1986.
236. Youssoufian, H.; Wong, C.; Aronis, S.; Platokoukis, H.; Kazazian,
H. H., Jr.; Antonarakis, S. E.: Moderately severe hemophilia A resulting
from glu-to-gly substitution in exon 7 of the factor VIII gene. Am.
J. Hum. Genet. 42: 867-871, 1988.
237. Zacharski, L. R.; Bowie, E. J. W.; Titus, J. L.; Owen, C. A.,
Jr.: Synthesis of antihemophilic factor (factor VIII) by leukocytes:
preliminary report. Mayo Clin. Proc. 43: 617-619, 1968.
238. Zimmerman, T. S.; Ratnoff, O. D.; Littell, A. S.: Detection
of carriers of classic hemophilia using an immunologic assay for antihemophilic
factor (factor VIII). J. Clin. Invest. 50: 255-258, 1971.
239. Zimmerman, T. S.; Ratnoff, O. D.; Powell, A. E.: Immunologic
differentiation of classic hemophilia (factor VIII deficiency) and
von Willebrand's disease, with observations on combined deficiencies
of antihemophilic factor and proaccelerin (factor V) and on an acquired
circulating anticoagulant against antihemophilic factor. J. Clin.
Invest. 50: 244-245, 1971.
Clinical Synopsis:
INHERITANCE:
X-linked recessive
SKELETAL:
[Limbs];
Hemarthroses;
Degenerative joint disease
SKIN, NAILS, HAIR:
[Skin];
Ecchymoses common;
Petechiae and purpura do not occur
LABORATORY ABNORMALITIES:
Factor VIII deficiency;
PTT prolonged;
PT normal;
Bleeding time normal;
Platelet count normal;
Platelet function normal
MISCELLANEOUS:
Partial factor VIII deficiency in heterozygous carriers;
Persistent bleeding after trauma
MOLECULAR BASIS:
Caused by mutations in the coagulation factor VIII gene (F8, 306700.0001)
Contributors:
Michael J. Wright - revised: 6/17/1999
Ada Hamosh - revised: 6/17/1999
Creation Date:
John F. Jackson: 6/15/1995
Edit Dates:
joanna: 05/07/2002
root: 6/24/1999
carol: 6/17/1999
kayiaros: 6/17/1999
Contributors:
Marla J. F. O'Neill - updated: 9/10/2009
cclk - updated: 5/18/2009
Marla J. F. O'Neill - updated: 4/30/2009
Cassandra L. Kniffin - updated: 12/8/2008
Cassandra L. Kniffin - updated: 12/3/2008
Marla J. F. O'Neill - updated: 7/17/2008
Cassandra L. Kniffin - updated: 11/13/2007
Cassandra L. Kniffin - updated: 4/24/2007
Victor A. McKusick - updated: 9/29/2006
Victor A. McKusick - updated: 6/20/2006
Cassandra L. Kniffin - updated: 5/18/2005
Victor A. McKusick - updated: 1/30/2004
Victor A. McKusick - updated: 12/23/2003
Victor A. McKusick - updated: 9/8/2003
Victor A. McKusick - updated: 8/28/2003
Victor A. McKusick - updated: 7/7/2003
Victor A. McKusick - updated: 1/10/2003
Victor A. McKusick - updated: 11/15/2002
Victor A. McKusick - updated: 6/3/2002
Victor A. McKusick - updated: 4/4/2002
Victor A. McKusick - updated: 3/14/2002
Victor A. McKusick - updated: 8/15/2001
Victor A. McKusick - updated: 2/14/2001
Victor A. McKusick - updated: 1/5/2001
Ada Hamosh - updated: 12/15/1999
Victor A. McKusick - updated: 10/21/1999
Victor A. McKusick - updated: 6/3/1999
Victor A. McKusick - updated: 2/14/1999
Victor A. McKusick - updated: 3/12/1997
Moyra Smith - updated: 1/29/1997
Stylianos E. Antonarakis - updated: 7/18/1996
Creation Date:
Victor A. McKusick: 6/4/1986
Edit Dates:
terry: 12/17/2009
wwang: 9/23/2009
terry: 9/10/2009
wwang: 5/20/2009
ckniffin: 5/18/2009
wwang: 5/5/2009
terry: 4/30/2009
wwang: 4/29/2009
terry: 3/27/2009
ckniffin: 12/8/2008
wwang: 12/4/2008
ckniffin: 12/3/2008
carol: 10/21/2008
terry: 9/12/2008
terry: 7/30/2008
wwang: 7/21/2008
terry: 7/17/2008
wwang: 7/14/2008
terry: 7/11/2008
wwang: 11/20/2007
ckniffin: 11/13/2007
wwang: 5/1/2007
ckniffin: 4/24/2007
wwang: 10/16/2006
alopez: 10/13/2006
terry: 9/29/2006
wwang: 6/20/2006
terry: 6/20/2006
wwang: 6/8/2005
wwang: 6/6/2005
ckniffin: 5/18/2005
carol: 4/8/2005
wwang: 3/24/2005
terry: 6/3/2004
carol: 3/17/2004
carol: 3/4/2004
tkritzer: 1/30/2004
cwells: 12/24/2003
terry: 12/23/2003
joanna: 10/6/2003
terry: 9/8/2003
tkritzer: 9/2/2003
tkritzer: 8/29/2003
tkritzer: 8/28/2003
alopez: 7/10/2003
terry: 7/7/2003
tkritzer: 1/14/2003
terry: 1/10/2003
cwells: 11/19/2002
terry: 11/15/2002
terry: 6/27/2002
cwells: 6/17/2002
terry: 6/3/2002
cwells: 4/15/2002
cwells: 4/10/2002
terry: 4/4/2002
alopez: 3/15/2002
terry: 3/14/2002
alopez: 1/3/2002
cwells: 9/7/2001
cwells: 8/24/2001
terry: 8/15/2001
mcapotos: 7/3/2001
mcapotos: 6/28/2001
terry: 6/26/2001
cwells: 2/20/2001
terry: 2/14/2001
mcapotos: 1/17/2001
mcapotos: 1/10/2001
terry: 1/5/2001
mcapotos: 7/25/2000
carol: 1/10/2000
alopez: 12/20/1999
terry: 12/15/1999
mgross: 10/28/1999
terry: 10/21/1999
kayiaros: 7/12/1999
kayiaros: 7/8/1999
jlewis: 6/15/1999
terry: 6/3/1999
terry: 5/20/1999
carol: 4/16/1999
carol: 2/14/1999
terry: 6/23/1998
terry: 6/18/1998
alopez: 5/21/1998
alopez: 8/4/1997
alopez: 7/10/1997
joanna: 7/9/1997
alopez: 7/3/1997
alopez: 6/27/1997
alopez: 6/26/1997
alopez: 6/11/1997
mark: 5/29/1997
jenny: 5/28/1997
mark: 5/28/1997
terry: 5/10/1997
terry: 4/29/1997
terry: 3/21/1997
terry: 3/17/1997
terry: 3/12/1997
terry: 3/10/1997
jamie: 2/4/1997
mark: 1/29/1997
terry: 1/29/1997
terry: 1/28/1997
mark: 1/27/1997
terry: 9/20/1996
terry: 7/24/1996
mark: 7/18/1996
terry: 7/16/1996
mark: 6/25/1996
mark: 4/26/1996
terry: 4/22/1996
mark: 3/31/1996
mark: 3/30/1996
terry: 3/12/1996
pfoster: 11/14/1995
mark: 11/13/1995
terry: 11/2/1995
phil: 5/3/1995
carol: 3/3/1995
warfield: 4/20/1994
OMIM
DBGET integrated database retrieval system
