Alternative titles; symbols
HGNC Approved Gene Symbol: F8
SNOMEDCT: 16872008, 26029002, 28293008; ICD10CM: D66; ICD9CM: 286.0;
Cytogenetic location: Xq28 Genomic coordinates (GRCh38) : X:154,835,792-155,022,723 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq28 | Hemophilia A | 306700 | X-linked recessive | 3 |
| Thrombophilia 13, X-linked, due to factor VIII defect | 301071 | 3 |
The F8 gene encodes coagulation factor VIII, a large plasma glycoprotein that functions in the blood coagulation cascade as a cofactor for the factor IXa (300746)-dependent activation of factor X (F10; 613872). Factor VIII is activated proteolytically by a variety of coagulation enzymes, including thrombin (F2; 176930). Factor VIII is tightly associated in the blood with von Willebrand factor (VWF; 613160), which serves as a protective carrier protein for factor VIII (summary by Toole et al., 1984; review by Hoyer, 1994).
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.
Toole et al. (1984) isolated clones corresponding to the F8 gene from a human cDNA library. Independently and simultaneously, Gitschier et al. (1984) and Wood et al. (1984) also cloned and expressed the F8 gene. The deduced precursor protein has 2,351 amino acids and a molecular mass of 267 kD. The leader sequence of the proprotein contains 19 amino acids, yielding a mature protein of 2,332 amino acids. The protein has an obvious domain structure, contains sequence repeats, and is structurally related to factor V (F5; 612309) and ceruloplasmin (CP; 117700). F8 has 3 copies of an A domain of 330 to 380 amino acids, a B domain of about 925 amino acids, and 2 C domains of about 160 amino acids. The domains are arranged A1-A2-B-A3-C1-C2. Both A and C repeats show conservation of cysteines, and the B region contains most potential N-glycosylation sites. Northern blot analysis detected a 9-kb F8 transcript.
The F8 gene is expressed in human liver, spleen, lymph nodes, and a variety of other tissues, but not in bone marrow, peripheral blood lymphocytes, or endothelial cells (Wion et al., 1985).
The F8 gene contains 26 exons and spans 186 kb (Gitschier et al., 1984).
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 F8 gene. The A or F8A gene (305423) was in reverse orientation to F8 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 F8 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 F8 gene transcription start site. Gene F8A, which is transcribed in the opposite direction to F8, is intronless and completely nested within intron 22. Approximately 500 kb upstream of the F8 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 F8 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 F8A; its first exon lies within intron 22 and is spliced to exons 23-26. The F8A and B genes are both expressed ubiquitously.
Having previously reported the existence of 5 CpG islands close to the F8 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 F8 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 (306700).
By in situ hybridization, Tantravahi et al. (1986) concluded that the F8 gene is located in the proximal part of chromosome 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 F8 probes did not hybridize but the DX13 and St14 did hybridize to the DNA of that cell line.
Patterson et al. (1987) showed that the G6PD (305900) and F8 genes lie within 500 kb of each other. Arveiler et al. (1989) showed that G6PD and F8 are in the same 290-kb pulsed field gel electrophoresis fragment, but 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 F8 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 F8 gene. The second site, which contains the RFLPs detected by 767, is located within 1.2 megabases of the F8 gene. Genetic data indicate tight linkage of F8 and DXS115; maximum lod = 8.30 at theta = 0.04.
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 F8 gene lies about 1.1 Mb from the telomere, with G6PD proximal to it, and about 1.5 Mb from the telomere. This contradicted the earlier impression that the gene is located in the proximal part of Xq28.
In a 9-year-old Malaysian female with de novo hemophilia A (306700) 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 F8 is oriented on the chromosome with its 5-prime region closest to the telomere.
Factor VII is a complex of a large inert carrier protein (VWF; 613160) and a noncovalently bound small fragment which contains the procoagulant active site. Zacharski et al. (1968) showed that leukocytes synthesize some factor VIII in vitro; however, 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.
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.
Ratnoff and Bennett (1973) reviewed the genetics of hereditary disorders of blood coagulation.
Hemophilia A
Gitschier et al. (1985) identified truncating mutations in the F8 gene (see, e.g., 300841.0001-300841.0003) as the basis for hemophilia A (306700). A severe hemophiliac with no detectable factor VIIIC activity had an R2307X mutation (300841.0001). Gitschier et al. (1986) found that the same codon was converted to glutamine (R2307Q; 300841.0042) in a mild hemophiliac with 10% of normal activity. 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.
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 had 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.
Levinson et al. (1987) used RNAse A cleavage and DNA sequencing of the altered region to identify a mutation in the F8 gene in a patient with hemophilia. The mutation 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.
Youssoufian et al. (1987) characterized 5 different partial deletions of the F8 gene in 83 patients with hemophilia. None had developed circulating inhibitors. One of the deletions occurred de novo in a germ cell of the maternal grandmother, while a second deletion occurred in a germ cell of a maternal grandfather. The findings indicated that de novo deletions of X-linked genes can occur in either male or female gametes. Youssoufian et al. (1988) reported 6 other partial F8 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.
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.
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.
Higuchi et al. (1988) found deletion of about 2,000 bases spanning exon 3 and part of IVS3 of the F8 gene 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 F8, 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 (300841.0046), in a patient with anti-factor VIII antibodies.
In a case of hemophilia A, Kazazian et al. (1988) described the first instance of insertional mutagenesis in man caused by a long inserted element (LINE) in the F8 gene. 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 F8 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 F8 gene 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.
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 F8 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.
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 a review, Antonarakis et al. (1995) collected the findings of more than 1,000 hemophilia subjects examined for F8 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.
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.
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.
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 (300841.0067), which accounted for 16.6% of all mutations and for 38% of those causing severe disease.
Inversion Mutations in Intron 22 of the F8 Gene
Intron 22 of the human F8 gene 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 F8 gene. Japanese showed 45% heterozygosity and Asian Indians showed 13%; polymorphism was not found in American blacks or Caucasians.
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 (300841.0067) as the cause of hemophilia A in 10 of 24 severely affected UK patients. These results confirmed predictions about the efficacy of the mRNA-based method suggested by Naylor et al. (1991), and also excluded hypotheses proposing that mutations outside the F8 gene are responsible for a large proportion of severe hemophilia A.
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 F8 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 F8 mRNA had become part of a hybrid message containing new multiexonic sequences expressed in normal cells. The novel sequences were not located in a YAC containing the whole F8 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.
The F8A gene (305423) is contained entirely within intron 22 of the F8 gene and is transcript in the reverse orientation from the F8 gene (Levinson et al., 1990). 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 F8 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.
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.
Inversion mutations resulting from recombinations between DNA sequences in the A gene in intron 22 of the F8 gene and 1 of 2 other A genes upstream to F8 have been shown to cause a large portion of cases. From data on more than 2,000 samples, Antonarakis et al. (1995) concluded 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. 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.
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 F8 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.
Hemophilia A with Inhibitors
Approximately 10 to 20% of patients with severe hemophilia A develop antibodies, known as inhibitors, to factor VIII following treatment with exogenous factor VIII. Most of these patients have nonsense mutations or deletions in the F8 gene (Antonarakis et al., 1995).
Antonarakis et al. (1985) identified several molecular defects in families with hemophilia A. One family had a deletion of about 80 kb in the F8 gene, whereas another had a single nucleotide change in the coding region of the gene, resulting in a nonsense codon and premature termination. In addition, they used 2 common polymorphic sites in the F8 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, affected persons developed inhibitors.
A variety of F8 gene mutations have been found in patients with hemophilia A due to inhibitors. Among 30 such cases, Antonarakis et al. (1995) found that 87 and 13% had different nonsense and missense mutations, respectively. F8 gene inversions do not seem to be a major predisposing factor for the development of inhibitors. Among severe hemophilia A cases, 16% of those without inversions and 20% of those with inversions developed inhibitors.
Schwaab et al. (1995) found that the probability of developing factor VIII inhibitors is greater in patients with large deletions in the F8 gene.
Viel et al. (2009) sequenced the F8 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 an 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.
Thrombophilia, X-Linked, due to Factor VIII Defect
Shen et al. (2013) evaluated F8 activity and F8 gene copy number in 179 patients with venous thromboembolism and 176 healthy controls. Patients with venous thromboembolism had significantly higher F8 activity compared to controls and also had a significantly greater number of copies of the F8 gene. F8 activity was also correlated to F8 gene copy number in patients versus controls, although this was not true for every individual patient. The F8 copy number was significantly higher in males compared to females.
In 7 individuals from 2 Italian families with thrombophilia (THPH13; 301071), Simioni et al. (2021) identified a tandem duplication in the factor VIII gene (300841.0272). The 2 families shared a 3-Mb haplotype, indicating a shared common ancestor. F8 mRNA was increased in patient lymphocytes. Increased transcriptional activity of fragments of the duplicated region was demonstrated by luciferase assay and was highest in a region (region C) that overlapped a major DNase I hypersensitivity cluster.
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.
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 (300841.0067). 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.
Early Mutation Detection Methods
Since point mutations in the F8 gene are responsible for most cases of hemophilia A and only a small proportion of these mutations could 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, 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 (tyr1709-to-cys and asn1922-to-asp). A previously described mutation in exon 24 (arg2209-to-gln) 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.
Higuchi et al. (1991) pointed out that whereas nearly all mutations resulting in mild to moderate hemophilia B could be detected by PCR and DGGE, these methods sufficed in only 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 F8 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.
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 (306700). 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.
In a severe case of hemophilia A (306700), 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).
In a patient with severe hemophilia A (306700), Gitschier et al. (1985) found deletion of about 22 kb including exon 26.
In a case of severe hemophilia A (306700) (JH5), Youssoufian et al. (1986) found change of codon 2135 from CGA to TGA, resulting in conversion of amino acid 2116 to stop.
In a case of severe hemophilia A (306700) (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).
In a case of severe hemophilia A (306700) (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 300841.0029, 300841.0047, and 300841.0049.
In a case of severe hemophilia A (306700) (JH8), Youssoufian et al. (1987) found deletion of exons 24 and 25.
In a case of severe hemophilia A (306700) (JH9), Youssoufian et al. (1987) found deletion of exons 23-25.
In a case of moderately severe hemophilia A (306700) (JH10), Youssoufian et al. (1987) found 'in-frame' deletion of exon 22.
In a case of severe hemophilia A (306700) (JH12), Antonarakis et al. (1995) found deletion of exon 26. The mother showed mosaicism for this mutation.
In a case of severe hemophilia A (306700) (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.
In a case of severe hemophilia A (306700) (JH14), Youssoufian et al. (1988) found a CGA to TGA change in codon 2166, resulting in a change in ARG2147 to a termination codon.
In a case of mild hemophilia A (306700) (JH17), Youssoufian et al. (1988) found the creation of a new splice donor site created in intron 4 by a GAA to AAA change.
In 2 cases of severe hemophilia A (306700) (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).
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 (306700) (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.
In a case of severe hemophilia A (306700) (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.
In a case of severe hemophilia A (306700) (JH22), Youssoufian et al. (1988) found deletion of exons 3-13.
In a case of severe hemophilia A (306700) (JH23), Youssoufian et al. (1988) found deletion of exons 4-25.
In a case of severe hemophilia A (306700) (JH24), Youssoufian et al. (1988) found deletion of exons 7-14.
In a normal individual (JH25), Woods-Samuels et al. (1989) found insertion of 0.7 kb of LINE sequence in intron 10.
In a patient with severe hemophilia A (306700) (JH26), Youssoufian et al. (1988) found deletion of exon 26. Also see Gitschier et al. (1985) and Bernardi et al. (1989).
In 2 brothers with severe hemophilia A (306700) (JH27, JH28), Kazazian et al. (1988) found insertion of 3.8 kb of LINE sequence in exon 14.
In a patient (JH29) with severe hemophilia A (306700) and a translocation t(X;17), Antonarakis et al. (1995) found deletion of exon 15.
In a patient with severe hemophilia A (306700) (JH31), Higuchi et al. (1990) found deletion of GA from codon 360 GAA in exon 8.
In a Japanese patient with mild hemophilia A (306700) (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.
{Antonarakis (unpublished observations)} reported a Japanese patient with mild hemophilia A (306700) with a CGA-to-CAA change t nucleotide 1960 in exon 18, resulting in substitution of glutamine for arginine at amino acid 1941. This mutation was also found in a Finnish patient by Levinson et al. (1990).
In a case of CRM-positive hemophilia A (306700) (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).
In a patient with severe hemophilia A (306700) (JH36), Higuchi et al. (1990) found a CAG-to-TAG change in codon 1705, causing replacement of glutamic acid 1686 by a stop signal.
In a patient with severe hemophilia A (306700) (JH37), Higuchi et al. (1989) found deletion of exon 14.
In a patient with moderately severe hemophilia A (306700) 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.
In a patient with mild hemophilia A (306700) (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.
In a patient with hemophilia A (306700) (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.
In a case of severe hemophilia A (306700) (JH1), Antonarakis et al. (1985) found deletion of exons 11-22.
(This allelic variant was originally entered into the database incorrectly as EX11-18DEL.)
In a case of severe hemophilia A (306700) (JH2), Antonarakis et al. (1985) found change in exon 18 from CGA to TGA which converted arg1960 to stop. Youssoufian et al. (1986) found the same mutation in another case of severe hemophilia A (JH3).
In a patient with severe hemophilia A (306700), Higuchi et al. (1989) found a deletion of exon 3 about 2 kb in length.
Levinson et al. (1990) found a deletion of 7 kb from IVS1 as a presumed normal variant of factor VIII.
In a patient with severe hemophilia A (306700), Higuchi et al. (1989) found a 35+ kb deletion removing exons 1 to 5.
In a patient with severe hemophilia A (306700), Lillicrap et al. (1986) found a 127+ kb deletion that removed exons 1 to 22.
In a patient with severe hemophilia A (306700), 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).
In a patient with severe hemophilia A (306700), 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.
This change was found in a case of moderately severe hemophilia A (306700) 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.
Gitschier et al. (1986) found this mutation in a case of mild hemophilia A (306700).
Levinson et al. (1990) found this mutation in a patient with less than 1% factor VIII activity and clinically severe hemophilia A (306700). The substitution was caused by a T-to-C transition at position 6555 in exon 23.
Levinson et al. (1987) found this mutation in a severe case of hemophilia A (306700).
Chan et al. (1989) found this mutation in a moderately severe case of hemophilia A (306700).
In a patient with severe hemophilia A (306700), Bardoni et al. (1988) found deletion of exons 15 to 18.
In a patient with severe hemophilia A (306700) with inhibitors, Higuchi et al. (1989) found deletion of exon 14.
In a patient with severe hemophilia A (306700), Gitschier (1988) found deletion of exons 23 to 25 as a result of a complex rearrangement with deletion-duplication.
In a patient with severe hemophilia A (306700) accompanied by inhibitors, Mikami (1988) found deletion of exon 14.
In a patient with severe hemophilia A (306700) with inhibitors, Higuchi et al. (1989) found deletion of exons 7 to 9.
In a patient with severe hemophilia A (306700), Levinson et al. (1990) found a 3- to 6-kb deletion removing exon 5.
In a patient with severe hemophilia A (306700), Levinson et al. (1990) found a deletion of about 10 kb removing exon 5.
In a patient with severe hemophilia A (306700), Briet et al. (1989) found a deletion of about 2 kb removing exon 5. Somatic and gonadal mosaicism was demonstrated in the mother.
In a patient with severe hemophilia A (306700) with inhibitors, Levinson et al. (1990) found a deletion of 3-10 kb removing exons 5 and 6.
Gitschier et al. (1986) found this mutation in a patient with severe hemophilia A (306700).
Traystman et al. (1990) demonstrated this mutation in patients with hemophilia A (306700).
In a patient with severe hemophilia A (306700), 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.
In a patient with severe hemophilia A (306700), 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).
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.
In a patient with mild hemophilia A (306700), 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.
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.
In a patient with sporadic severe hemophilia A (306700), 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.
In a sporadic case of mild hemophilia A (306700), Paynton et al. (1991) demonstrated a C-to-T transition that resulted in mutation 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.
In a study of the molecular defects responsible for crossreacting material-positive hemophilia A (306700), 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.
See 300841.0065.
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 (306700), 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.
Bidichandani et al. (1994) studied 15 randomly selected hemophilia A (306700) 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.
In 2 patients with hemophilia A (306700), Pattinson et al. (1990) identified mutation 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).
Antonarakis et al. (1995) reported this mutation in a patient with less than 1% factor VIII activity and severe hemophilia A (306700). The mutation is caused by a CTG-to-CGG transversion at codon 7 in exon 1 of the A1 domain, resulting in arginine for leucine-7.
Diamond et al. (1992) found this mutation in a patient with mild hemophilia A (306700). 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.
Antonarakis et al. (1995) reported in a patient with severe hemophilia A (306700) the deletion of 89 nucleotides from codon 14 to 29 in exon 1, resulting in a frameshift.
Antonarakis et al. (1995) reported this substitution in 2 patients with less than 1% factor VIII activity and severe hemophilia A (306700). The mutation is caused by a GGT-to-TGT transversion at codon 22 in exon 1 of the A1 domain, resulting in cysteine for glycine-22.
In a patient with severe hemophilia A (306700), Lin et al. (1993) identified the insertion of 10 nucleotides (TTCCATTCAA) resulting in a frameshift downstream from codon 38 in exon 2.
In a patient with severe hemophilia A (306700), Lin et al. (1993) identified the deletion of 2 nucleotides (AA) resulting in a frameshift downstream from codon 48 in exon 2.
Antonarakis et al. (1995) reported in a patient with severe hemophilia A (306700) the deletion of 4 nucleotides (GTTT) resulting in a frameshift downstream from codon 50 in exon 2.
In a patient with severe hemophilia A (306700), Antonarakis et al. (1995) reported the deletion of 2 nucleotides (GT) resulting in a frameshift downstream from codon 102 or 3 in exon 3.
Higuchi et al. (1991) identified in a patient with severe hemophilia A (306700) the deletion of 23 nucleotides resulting in a frameshift downstream from codon 104 in exon 3.
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 (306700).
Antonarakis et al. (1995) reported this gly70-to-asp mutation in a patient with less than 1% factor VIII activity and severe hemophilia A (306700). The mutation is caused by a GGT-to-GAT transition at codon 70 in exon 3 of the A1 domain.
Diamond et al. (1992) found this mutation in a patient with mild hemophilia A (306700). The mutation is caused by a GGT-to-GTT transversion at codon 73 in exon 3 of the A1 domain, resulting in valine for glycine-73.
Antonarakis et al. (1995) reported this val80-to-asp mutation in a patient with less than 1% factor VIII activity and severe hemophilia A (306700). The mutation is caused by a GTT-to-GAT transversion at codon 80 in exon 3 of the A1 domain.
Diamond et al. (1992) found this val85-to-asp mutation in a patient with mild hemophilia A (306700). The mutation is caused by a GTC-to-GAC transversion at codon 85 in exon 3 of the A1 domain.
Higuchi et al. (1991) found this lys89-to-thr mutation in a patient with mild hemophilia A (306700). The mutation is caused by an AAG-to-ACG transversion at codon 89 in exon 3 of the A1 domain.
Higuchi et al. (1991) found this mutation in a patient with moderate hemophilia A (306700). The mutation is caused by an ATG-to-GTG transition at codon 91 in exon 3 of the A1 domain, resulting in valine for methionine-91.
Antonarakis et al. (1995) reported this mutation in a patient with less than 1% factor VIII activity and severe hemophilia A (306700). 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.
In a patient with less than 1% factor VIII activity and severe hemophilia A (306700), Lin et al. (1993) identified a GGA-to-CGA transversion at codon 111 in exon 3 of the A1 domain of the F8 gene, resulting in arginine for glycine-111. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), the mutation is designated gly130-to-arg (G130R).
Antonarakis et al. (1995) reported a glu113-to-asp mutation in a patient with less than 1% factor VIII activity, severe hemophilia A (306700) and inhibitors. It is caused by a GAA-to-GAC transversion at codon 113 in exon 4 of the A1 domain of factor VIII. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated glu132-to-asp (E132D).
Antonarakis et al. (1995) reported this tyr114-to-cys mutation in a patient with 6.3% factor VIII activity, 10.7% factor VIII antigen, and mild hemophilia A (306700). The mutation 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.
Antonarakis et al. (1995) reported this mutation in a patient with less than 1% factor VIII activity and severe hemophilia A (306700). The mutation 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.
Antonarakis et al. (1995) reported this mutation in a patient with 2% factor VIII activity, 10.7% factor VIII antigen, and moderate hemophilia A (306700). The mutation is caused by an ACC-to-ATC transition at codon 118 in exon 4 of the A1 domain, resulting in isoleucine for threonine-118. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated thr137-to-ile (T137I).
Diamond et al. (1992) found this gly145-to-val mutation in a patient with mild hemophilia A (306700). The mutation is caused by a GGT-to-GTT transversion at codon 145 in exon 4 of the A1 domain.
Lin et al. (1993) found a pro146-to-ser mutation in a patient with less than 1% factor VIII activity and severe hemophilia A (306700). The mutation is caused by a CCA-to-TCA transition at codon 146 in exon 4 of the A1 domain.
Diamond et al. (1992) found this mutation in 5 patients with 3.5-8.5% factor VIII activity, 6-35.9% factor VIII antigen, and moderate to mild hemophilia A (306700). A GTG-to-ATG transition at codon 162 in exon 4 of the A1 domain resulted in a val162-to-met change.
Higuchi et al. (1991) found this lys166-to-thr mutation in a patient with 19% factor VIII activity and mild hemophilia A (306700). The mutation is caused by an AAA-to-ACA transversion at codon 166 in exon 4 of the A1 domain.
Antonarakis et al. (1995) reported this mutation in a patient with 2% factor VIII activity, 8.5% factor VIII antigen, and moderate hemophilia A (306700). The mutation 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.
Higuchi et al. (1991) found this mutation in a patient with 3.2% factor VIII activity and moderate hemophilia A (306700). The mutation is caused by a GGG-to-TGG transversion at codon 205 in exon 5 of the A1 domain, resulting in tryptophan for glycine-205.
In a patient with severe hemophilia A (306700), Lin et al. (1993) identified the deletion of 2 nucleotides (AG) resulting in a frameshift downstream from codon 210-211 in exon 6.
In a patient with less than 1% factor VIII activity and severe hemophilia A (306700), 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.
In a patient with 3-4% factor VIII activity and moderate hemophilia A (306700), Bidichandani et al. (1994) identified mutation of A to G at the third nucleotide of the donor splice site of intron 6, which resulted in abnormal splicing.
Antonarakis et al. (1995) reported a patient with less than 1% factor VIII activity and severe hemophilia A (306700) who had a G-to-C transversion. The mutation was in the first nucleotide of the acceptor splice site of intron 6 and resulted in abnormal splicing ({Antonarakis and Kazazian, unpublished}).
Eckhardt et al. (2013) noted that a gly266-to-glu (G266E) mutation in the F8 gene (gly247-to-glu in the mature protein) had been found in patients with hemophilia A (306700).
Antonarakis et al. (1995) had reported this mutation as a gly247-to-gln substitution caused by a GGA-to-GAA transition at codon 247 in exon 7 of the A1 domain. The patient had less than 1% factor VIII activity and severe hemophilia A.
In a patient with hemophilia A (306700), Antonarakis et al. (1995) reported mutation of TGG-to-TGA at codon 255 in exon 7, resulting in a stop codon. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated trp274-to-ter (W274X).
Antonarakis et al. (1995) reported this mutation in a patient with less than 1% factor VIII activity and severe hemophilia A (306700). The mutation is caused by a GGA-to-AGA transition at codon 259 in exon 7 of the A1 domain, resulting in arginine for glycine-259. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated gly6278-to-arg (G278R).
In a patient with severe hemophilia A (306700), Antonarakis et al. (1995) reported the deletion of 1 nucleotide (T) resulting in a frameshift downstream from codon 264 in exon 7.
Higuchi et al. (1991) found this mutation in a patient with mild hemophilia A (306700). The mutation is caused by a GTG-to-GGG transversion at codon 266 in exon 7 of the A1 domain, resulting in glycine for valine-266.
Antonarakis et al. (1995) reported this mutation in a patient with 4-4.8% factor VIII activity, 20-40% factor VIII antigen, and moderate hemophilia A (306700). The mutation is caused by a ACA-to-ATA transition at codon 275 in exon 7 of the A1 domain, resulting in isoleucine for threonine-275.
Pieneman et al. (1993) found this mutation in a patient with 8-12% factor VIII activity and mild hemophilia A (306700). The mutation is caused by a AAC-to-ATC transversion at codon 280 in exon 7 of the A1 domain, resulting in isoleucine for asparagine-280.
Higuchi et al. (1991) found this mutation in a patient with less than 1% factor VIII activity, 18% factor VIII antigen, and severe hemophilia A (306700). 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).
Antonarakis et al. (1995) reported this mutation in 2 patients with less than 1% factor VIII activity and severe hemophilia A (306700). 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.
In a patient with severe hemophilia A (306700), Antonarakis et al. (1995) reported the deletion of 1 nucleotide (G), resulting in a frameshift downstream from codon 283 in exon 7.
McGinniss et al. (1993) found this substitution in a patient with 37% factor VIII activity, 106% factor VIII antigen and mild hemophilia A (306700). The mutation 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.
Higuchi et al. (1991) found this mutation in 3 patients with 7-21.5% factor VIII activity, 2-17.9% factor VIII antigen, and mild hemophilia A (306700). An ACT-to-GCT transition at codon 295 in exon 7 of the A1 domain results in alanine for threonine-295.
Higuchi et al. (1991) found this mutation in 3 patients with 7-21.5% factor VIII activity, 2-17.9% factor VIII antigen, and mild hemophilia A (306700). The mutation is caused by an ACT-to-GCT transition at codon 295 in exon 7 of the A1 domain, resulting in alanine for threonine-295. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated thr314-to-ala (T314A).
(Antonarakis et al. (1995)) reported in a patient with severe hemophilia A (306700) the deletion of 1 nucleotide (G), resulting in a frameshift downstream from codon 296 in exon 7.
Antonarakis et al. (1995) reported this mutation in a patient with less than 1% factor VIII activity and severe hemophilia A (306700). The mutation is caused by a CTG-to-CCG transition at codon 308 in exon 7 of the A1 domain, resulting in proline for leucine-308.
In 1 patient with hemophilia A (306700), Lin et al. (1993) identified a TAT-to-TAA substitution at codon 323 in exon 8, resulting in a stop codon. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated tyr342-to-ter (W342X).
Antonarakis et al. (1995) reported this mutation in a patient with less than 1% factor VIII activity and severe hemophilia A (306700). The mutation is caused by a TGT-to-TAT transition at codon 329 in exon 8 of the A1 domain, resulting in tyrosine for cysteine-329.
Antonarakis et al. (1995) reported this mutation in a patient with 2.6% factor VIII activity, 3.2% factor VIII antigen, and moderate hemophilia A (306700). The mutation is caused by a TGT-to-TCT transversion at codon 329 in exon 8 of the A1 domain, resulting in serine for cysteine-329. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated cys348-to-ser (C348S).
In a patient with severe hemophilia A (306700), Higuchi et al. (1990) identified the deletion of 2 nucleotides (GA) resulting in a frameshift downstream from codon 341 in exon 8.
In 1 patient with hemophilia A (306700), Acquila et al. (1993) identified a TCA-to-TAA substitution at codon 373 in exon 8, resulting in a stop codon. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated ser392-to-ter (S392X).
Acquila et al. (1993) found this mutation in a patient with 8% factor VIII activity and mild hemophilia A (306700). The mutation 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.
Johnson et al. (1994) found this mutation in a patient with 10% factor VIII activity, 100% factor VIII antigen, and mild hemophilia A (306700). The mutation 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.
In a patient with severe hemophilia A (306700), Antonarakis et al. (1995) reported the deletion of 2 nucleotides (AA), resulting in a frameshift downstream from codon 381-382 in exon 8.
Lin et al. (1993) found this mutation in a patient with less than 1% factor VIII activity and severe hemophilia A (306700). The mutation is caused by an ATT-to-AGT transversion at codon 386 in exon 8 of the A2 domain, resulting in serine for isoleucine-386.
Antonarakis et al. (1995) reported this mutation in 2 patients with less than 1-3.3% factor VIII activity and severe to moderate hemophilia A (306700). The mutation 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.
Higuchi et al. (1991) found this mutation in 2 patients with 5-10.5% factor VIII activity and moderate to mild hemophilia A (306700). The mutation is caused by a TTG-to-TTT transversion at codon 412 in exon 9 of the A2 domain, resulting in phenylalanine for leucine-412.
In a patient with severe hemophilia A (306700), Lin et al. (1993) identified the deletion of 1 nucleotide (G), resulting in a frameshift downstream from leucine-412 in exon 9.
Higuchi et al. (1991) found this mutation in a patient with less than 1% factor VIII activity, 5% factor VIII antigen, and severe hemophilia A (306700). The mutation is caused by a AAA-to-AGA transition at codon 425 in exon 9 of the A2 domain, resulting in arginine for lysine-425.
Pieneman et al. (1993) found this mutation in a patient with 4% factor VIII activity and moderate hemophilia A (306700). The mutation is caused by a TAC-to-AAC transversion at codon 431 in exon 9 of the A2 domain, resulting in asparagine for tyrosine-431.
Higuchi et al. (1991) found this mutation in a patient with mild hemophilia A (306700). The mutation is caused by a TAT-to-CAT transition at codon 473 in exon 10 of the A2 domain, resulting in histidine for tyrosine-473.
Higuchi et al. (1991) found this mutation in 2 patients with 2.7-3.5% factor VIII activity and moderate hemophilia A (306700). The mutation is caused by a TAT-to-TGT transition at codon 473 in exon 10 of the A2 domain, resulting in cysteine for tyrosine-473.
Antonarakis et al. (1995) reported this mutation in a patient with 5-5.7% factor VIII activity, 6.9-8.8% factor VIII antigen, and mild hemophilia A (306700). The mutation is caused by an ATC-to-ACC transition at codon 475 in exon 10 of the A2 domain, resulting in threonine for isoleucine-475.
Naylor et al. (1993) found this mutation in a patient with 2% factor VIII activity and moderate hemophilia A (306700). The mutation was caused by a GGA-to-AGA transition in the F8 gene, resulting in a gly479-to-arg substitution. Antonarakis et al. (1995) stated that this mutation occurred in exon 10 of the A2 domain and had been reported in 2 other patients with hemophilia A. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated gly498-to-arg (G498R).
In a patient with severe hemophilia A (306700), 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.
In a patient with mild hemophilia A (306700), 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.
In a patient with severe hemophilia A (306700), Economou et al. (1992) identified the insertion of 1 nucleotide (G), resulting in a frameshift downstream from codon 513 or 514 in exon 11.
Antonarakis et al. (1995) reported this mutation in a patient with 6% factor VIII activity, 61% factor VIII antigen, and moderate hemophilia A (306700). The mutation 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.
Higuchi et al. (1991) found this mutation in a patient with 9.5-38% factor VIII activity, 43-245% factor VIII antigen, and mild hemophilia A (306700). The mutation 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).
Higuchi et al. (1991) found this mutation in 3 patients with 4.2-6.7% factor VIII activity and moderate to mild hemophilia A (306700). The mutation 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).
Higuchi et al. (1991) found this mutation in a patient with 9.2% factor VIII activity and mild hemophilia A (306700). The mutation is caused by a CGC-to-GGC transversion at codon 531 in exon 11 of the A2 domain, resulting in glycine for arginine-531.
Antonarakis et al. (1995) reported this mutation in a patient with 23.5-32% factor VIII activity, 20-33.2% factor VIII antigen and mild hemophilia A (306700). The mutation 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.
Antonarakis et al. (1995) reported this mutation in 2 patients with mild hemophilia A (306700). The mutation is caused by a AGT-to-GGT transition at codon 535 in exon 11 of the A2 domain, resulting in glycine for serine-535.
Higuchi et al. (1991) found this mutation in a patient with less than 1% factor VIII activity, 5% factor VIII antigen, and severe hemophilia A (306700). The mutation 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.
In a patient with hemophilia A (306700), Diamond et al. (1992) identified a GAA-to-TAA substitution at codon 557 in exon 11, resulting in a stop codon.
McGinniss et al. (1993) found this mutation in a patient with 21% factor VIII activity, 175% factor VIII antigen, and mild hemophilia A (306700). The mutation is caused by a TCT-to-TTT transition at codon 558 in exon 11 of the A2 domain, resulting in phenylalanine for serine-558.
Higuchi et al. (1991) found this mutation in 2 patients with 6.8% factor VIII activity and moderate to mild hemophilia A (306700). The mutation 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).
Reiner and Thompson (1992) found this mutation in 5 patients with less than 1% factor VIII activity and severe hemophilia A (306700). The mutation 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).
In 5 patients with hemophilia A (306700), 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).
Antonarakis et al. (1995) reported this mutation in a patient with hemophilia A (306700). The mutation is caused by a AGC-to-ATC transversion at codon 584 in exon 12 of the A2 domain, resulting in isoleucine for serine-584.
Lin et al. (1993) found this mutation in a patient with less than 1% factor VIII activity and severe hemophilia A (306700). The mutation is caused by a TGG-to-TGC transversion at codon 585 in exon 12 of the A2 domain, resulting in cysteine for tryptophan-585. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated trp604-to-cys (W604C).
Lin et al. (1993) found this mutation in a patient with less than 1% factor VIII activity and severe hemophilia A (306700). The mutation is caused by a TAC-to-TCC transversion at codon 586 in exon 12 of the A2 domain, resulting in serine for tyrosine-586.
Higuchi et al. (1991) found this mutation in a patient with mild to moderate hemophilia A (306700). The mutation 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).
Antonarakis et al. (1995) reported this mutation in a patient with hemophilia A (306700). The mutation is caused by a AAC-to-AGC transition at codon 612 in exon 12 of the A2 domain, resulting in serine for asparagine-612.
In a patient with mild hemophilia A (306700), Antonarakis et al. (1995) reported a G-to-A transition. The mutation is at the fifth nucleotide of the donor splice site of intron 12 and results in abnormal splicing.
McGinniss et al. (1993) found this mutation in a patient with 5% factor VIII activity, 138% factor VIII antigen, and mild hemophilia A (306700). The mutation is caused by a GTG-to-GCG transition at codon 634 in exon 13 of the A2 domain, resulting in alanine for valine-634.
McGinniss et al. (1993) found a val634-to-met mutation in 2 patients with less than 1% factor VIII activity, 175% factor VIII antigen, and severe hemophilia A (306700). The mutation is caused by a GTG-to-ATG transition at codon 634 in exon 13 of the A2 domain.
In 2 patients with hemophilia A (306700) (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. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated trp655-to-cys (W604C).
Higuchi et al. (1991) found this mutation in a patient with 14% factor VIII activity, 25% factor VIII antigen, and mild hemophilia A (306700). The mutation is caused by a GCA-to-GTA transition at codon 644 in exon 13 of the A2 domain, resulting in valine for alanine-644.
In a patient with 1.4% factor VIII activity, 12% factor VIII antigen, and severe hemophilia A (306700), 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.
Antonarakis et al. (1995) reported this mutation in a patient with 5.1% factor VIII activity, 50.5% factor VIII antigen, and moderate hemophilia A (306700). The mutation is caused by a TTC-to-CTC transition at codon 658 in exon 13 of the A2 domain, resulting in leucine for phenylalanine-658. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated phe677-to-leu (F677L).
Diamond et al. (1992) found this mutation in a patient with mild hemophilia A (306700). The mutation 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.
Higuchi et al. (1991) found this mutation in 3 patients with a mild to moderate hemophilia A (306700). The mutation 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).
Antonarakis et al. (1995) reported this glu720-to-lys mutation in 2 patients with 12.5-30% factor VIII activity, less than 20% factor VIII antigen, and a mild hemophilia A (306700). The mutation 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.
In a patient with hemophilia A (306700), 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.
In a patient with severe hemophilia A (306700), 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.
In a patient with severe hemophilia A (306700), Lin et al. (1993) identified the deletion of 2 nucleotides (AG) that results in a frameshift downstream from codon 969 in exon 14.
Higuchi et al. (1991) and McGinniss et al. (1993) found this mutation in a patient with 2.4% factor VIII activity, 15% factor VIII antigen, and moderate hemophilia A (306700). The mutation 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.
In a patient with severe hemophilia A (306700), Lin et al. (1993) identified the deletion of 2 nucleotides (AA) resulting in a frameshift downstream from codon 1164 in exon 14.
In 2 patients with severe hemophilia A (306700), Lin et al. (1993) identified the deletion of 1 nucleotide (A) resulting in a frameshift downstream from codon 1194 in exon 14.
In a patient with severe hemophilia A (306700), Naylor et al. (1993) identified the deletion of 1 nucleotide (C) resulting in a frameshift downstream from codon 1212 in exon 14.
In a patient with severe hemophilia A (306700), Lin et al. (1993) identified the insertion of 2 nucleotides (AA) resulting in a frameshift downstream from codon 1324 in exon 14.
In a patient with severe hemophilia A (306700), Lin et al. (1993) identified the deletion of 4 nucleotides (TAGA) resulting in a frameshift downstream from codons 1355-6 in exon 14.
In a patient with severe hemophilia A (306700), Higuchi et al. (1991) identified the insertion of 1 nucleotide (A) resulting in a frameshift downstream from codon 1395 in exon 14.
Antonarakis et al. (1995) reported in a patient with severe hemophilia A (306700) the deletion of 5 nucleotides (CTCTT) resulting in a frameshift downstream from codons 1412-4 in exon 14.
In a patient with severe hemophilia A (306700), Naylor et al. (1993) identified the deletion of 4 nucleotides (AAGA) resulting in a frameshift downstream from codons 1422-5 in exon 14.
Higuchi et al. (1991) identified in 2 patients with severe hemophilia A (306700) the insertion of 1 nucleotide (A) between codons 1458 and 1460 in exon 14 resulting in a frameshift.
In 2 patients with severe hemophilia A (306700), 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.
In a patient with severe hemophilia A (306700), Higuchi et al. (1991) identified the deletion of 2 nucleotides (GA) between codons 1555 and 1556 in exon 14 resulting in a frameshift.
In a patient with severe hemophilia A (306700), Lin et al. (1993) identified the insertion of 1 nucleotide (A) resulting in a frameshift downstream from codon 1590 in exon 14.
In a patient with severe hemophilia A (306700), Lin et al. (1993) identified the deletion of 1 nucleotide (C) resulting in a frameshift downstream from codon 1601 in exon 14.
In a patient with hemophilia A (306700), Lavergne et al. (1992) identified the substitution of GAG-to-TAG at codon 1615 in exon 14, resulting in a stop codon.
Schwaab et al. (1993) found this mutation in 3 patients with 7-11% factor VIII activity, 130-165% factor VIII antigen, and mild hemophilia A (306700). The mutation 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.
In 2 patients with hemophilia A (306700) 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).
Reiner and Thompson (1992) found this mutation in a patient with 17% factor VIII activity and mild hemophilia A (306700). The mutation 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.
In a patient with less than 1% factor VIII activity, less than 2.5% factor VIII antigen, and severe hemophilia A (306700), 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.
Antonarakis et al. (1995) reported this mutation in 4 patients with 21-26% factor VIII activity, 14.5-26% factor VIII antigen, and mild hemophilia A (306700). The mutation was caused by a GGA-to-AGA transition at codon 1750 in exon 15 of the A3 domain, resulting in arginine for glycine-1750. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated gly1769-to-arg (G1769R).
Antonarakis et al. (1995) reported this mutation in a patient with 5% factor VIII activity, 1.5% factor VIII antigen, and moderate hemophilia A (306700). The mutation was caused by a TTG-to-GTG transversion at codon 1756 in exon 15 of the A3 domain, resulting in valine for leucine-1756.
Antonarakis et al. (1995) reported this mutation in a patient with 18.5% factor VIII activity, and mild hemophilia A (306700). The mutation was caused by a TTG-to-TTC transversion at codon 1756 in exon 15 of the A3 domain, resulting in phenylalanine for leucine-1756. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated leu1775-to-phe (L1775F).
Lin et al. (1993) found this mutation in a patient with less than 1% factor VIII activity and severe hemophilia A (306700). The mutation 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.
Higuchi et al. (1991) found this mutation in 4 patients with 2-2.5% factor VIII activity, 4.7-5.4% factor VIII antigen, and moderate hemophilia A (306700). The mutation 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).
Jonsdottir et al. (1992) found this mutation in a patient with 4-7% factor VIII activity and mild hemophilia A (306700). The mutation 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.
Antonarakis et al. (1995) reported this mutation in a patient with 6% factor VIII activity and mild hemophilia A (306700). The mutation was caused by a CGT-to-GGT transversion at codon 1781 in exon 16 of the A3 domain, resulting in glycine for arginine-1781.
Higuchi et al. (1991) found this mutation in a patient with less than 1% factor VIII activity and clinically a severe hemophilia A (306700). The mutation was caused by a TCC-to-TAC transversion at codon 1784 in exon 16 of the A3 domain, resulting in tyrosine for serine-1784.
Diamond et al. (1992) and Lin et al. (1993) found this mutation in 3 patients with 7.2% factor VIII activity and mild hemophilia A (306700). The mutation was caused by a CTT-to-TTT transition at codon 1789 in exon 16 of the A3 domain, resulting in phenylalanine for leucine-1789.
In a patient with hemophilia A (306700) and inhibitors, Lin et al. (1993) identified the substitution of CAG-to-TAG at codon 1796 in exon 16, resulting in a stop codon.
Lin et al. (1993) found this mutation in a patient with 4.6% factor VIII activity and moderate hemophilia A (306700). The mutation is caused by an ATG-to-ATA transition at codon 1823 in exon 16 of the A3 domain, resulting in isoleucine for methionine-1823.
Higuchi et al. (1991) found this mutation in a patient with 15% factor VIII activity and mild hemophilia A (306700). The mutation was caused by a CCC-to-TCC transition at codon 1825 in exon 16 of the A3 domain, resulting in serine for proline-1825.
Economou et al. (1992) found this mutation in a patient with mild hemophilia A (306700). The mutation was caused by an ACT-to-CCT transversion at codon 1826 in exon 16 of the A3 domain, resulting in proline for threonine-1826.
In 2 patients with hemophilia A (306700) and inhibitors, Lin et al. (1993) identified the mutation AAA to TAA at codon 1827 in exon 16, resulting in a stop codon.
Lin et al. (1993) found this mutation in a patient with 18% factor VIII activity and mild hemophilia A (306700). The mutation was caused by a GCC-to-GTC transition at codon 1834 in exon 16 of the A3 domain, resulting in valine for alanine-1834.
In 2 patients with 9-18% factor VIII activity, 5.9% factor VIII antigen, and mild hemophilia A (306700), 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.
Antonarakis et al. (1995) reported this mutation in a patient with less than 1% factor VIII activity and severe hemophilia A (306700). The mutation 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.
Antonarakis et al. (1995) reported this mutation in a patient with less than 1% factor VIII activity and severe hemophilia A (306700). The mutation 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.
Higuchi et al. (1991) found this mutation in a patient with 1-5% factor VIII activity and moderate hemophilia A (306700). The mutation was caused by a CAC-to-CGC transition at codon 1848 in exon 17 of the A3 domain, resulting in arginine for histidine-1848.
Antonarakis et al. (1995) reported this mutation in a patient with less than 1% factor VIII activity and severe hemophilia A (306700). The mutation was caused by a CCC-to-CGC transversion at codon 1854 in exon 17 of the A3 domain, resulting in arginine for proline-1854.
Antonarakis et al. (1995) reported in 1 patient with severe hemophilia A (306700) the insertion of 1 nucleotide (T) resulting in a frameshift downstream from codon 1855 in exon 17.
In 1 patient with hemophilia A (306700) and inhibitors, Naylor et al. (1993) identified the substitution of CAG-to-TAG at codon 1874 in exon 17, resulting in a stop codon.
Lin et al. (1993) found this mutation in a patient with less than 1% factor VIII activity and severe hemophilia A (306700). The mutation 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.
Higuchi et al. (1991) identified in 1 patient with severe hemophilia A (306700) the insertion of 1 nucleotide (A) at codon 1907 in exon resulting in a frameshift.
Higuchi et al. (1991) and Diamond et al. (1992) identified this mutation in 2 patients with less than 1% factor VIII activity and severe-to-moderate hemophilia A (306700). The mutation was an AAT-to-AGT transition at codon 1922 in exon 18 of the F8 gene, resulting in an asn1922-to-ser (N1922S) substitution in the A3 domain of the protein.
Summers et al. (2011) noted that N1922 lies at the interface of 2 A3 subdomains in F8 and that the A3 and adjacent C1 domains form an extensive hydrophobic interface. By expression in baby hamster kidney cells, they found that F8 with the N1922S mutation (F8-N1922S) was weakly secreted compared with wildtype F8, although secreted F8-N1922S showed normal or near-normal activity. Wildtype F8 followed the classic secretory pathway; however, F8-N1922S was delayed in the endoplasmic reticulum (ER), prior to processing and packaging in the Golgi. Use of conformation-specific monoclonal antibodies revealed that the delay in the ER was due to a defect in folding of the A3 domain and the adjacent C1 domain. Summers et al. (2011) concluded that the N1922S substitution results in poor secretion of a functional protein.
Nafa et al. (1992) found this mutation in a patient with 7% factor VIII activity and moderate hemophilia A (306700). The mutation was caused by a CGA-to-CTA transversion at codon 1941 in exon 18 of the A3 domain, resulting in leucine for arginine-1941.
In a patient with hemophilia A (306700), Lin et al. (1993) identified the substitution of TGG-to-TAG at codon 1942 in exon 18, resulting in a stop codon. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated trp1961-to-ter (W1961X).
David et al. (1994) found this mutation in a patient with 7.4% factor VIII activity, 46.7% factor VIII antigen, and moderate hemophilia A (306700). The mutation 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.
Antonarakis et al. (1995) reported this mutation in a patient with 6% factor VIII activity and moderate hemophilia A (306700). The mutation was caused by a GGA-to-GTA transversion at codon 1960 in exon 18 of the A3 domain, resulting in valine for glycine-1960.
Antonarakis et al. (1995) reported this mutation in a patient with 15.5% factor VIII activity, 7.8% factor VIII antigen, and mild hemophilia A (306700). The mutation was caused by a CAT-to-TAT transition at codon 1961 in exon 18 of the A3 domain, resulting in tyrosine for histidine-1961.
In 7 patients with hemophilia A (306700) (3 with inhibitors), Reiner and Thompson (1992) identified the mutation 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).
Antonarakis et al. (1995) identified in 2 patients with severe hemophilia A (306700) the deletion of 1 nucleotide (A) resulting in a frameshift downstream from codon 1967-1968 in exon 19.
Antonarakis et al. (1995) reported in 1 patient with severe hemophilia A (306700) the deletion of 1 nucleotide (G) resulting in a frameshift downstream from codon 1998 in exon 19.
In 1 patient with hemophilia A (306700), Naylor et al. (1993) identified the mutation of GAA to TAA at codon 1987 in exon 19, resulting in a stop codon and exon 19 skipping.
Higuchi et al. (1991) and Antonarakis et al. (1995) reported this mutation in 3 patients with less than 1-3.4% factor VIII activity and moderate to severe hemophilia A (306700). The mutation 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.
Antonarakis et al. (1995) reported this mutation in a patient with 5% factor VIII activity, 3.3% factor VIII antigen, and moderate hemophilia A (306700). The mutation was caused by a AAT-to-AGT transition at codon 2019 in exon 19 of the A3 domain, resulting in serine for asparagine-2019.
Diamond et al. (1992) found this mutation in a patient with moderate hemophilia A (306700). The mutation was caused by a TGG-to-CGG transition at codon 2046 in exon 21 of the C1 domain, resulting in arginine for tryptophan-2046. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated trp2065-to-arg (W2065R).
Antonarakis et al. (1995) reported this mutation in a patient with less than 1% factor VIII activity and severe hemophilia A (306700). The mutation was caused by a TCT-to-TTT transition at codon 2069 in exon 21 of the C1 domain, resulting in phenylalanine for serine-2069.
Antonarakis et al. (1995) found this mutation in 2 patients with 4.5-9% factor VIII activity, 1.7-15.2% factor VIII antigen, and mild hemophilia A (306700). The mutation 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.
Antonarakis et al. (1995) reported this mutation in 2 patients with 7-11% factor VIII activity, 5.3% factor VIII antigen, and mild hemophilia A (306700). The mutation was caused by a TTT-to-TTG transversion at codon 2101 in exon 22 of the C1 domain, resulting in leucine for phenylalanine-2101. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated phe2120-to-leu (F2120L).
Naylor et al. (1993) found this mutation in a patient with 14% factor VIII activity and mild hemophilia A (306700). The mutation was caused by a TAT-to-TGT transition at codon 2105 in exon 22 of the C1 domain, resulting in cysteine for tyrosine-2105. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated tyr2124-to-cys (Y2124C).
Antonarakis et al. (1995) reported this mutation in 3 patients with 3-8% factor VIII activity, 9.2-13.2% factor VIII antigen, and mild to moderate hemophilia A (306700). The mutation was caused by a TCC-to-TAC transversion at codon 2119 in exon 22 of the C1 domain, resulting in tyrosine for serine-2119.
Antonarakis et al. (1995) identified in 1 patient with severe hemophilia A (306700) the deletion of 2 nucleotides (TC) resulting in a frameshift downstream from serine-2119 in exon 22.
Tuddenham et al. (1991) identified in 1 patient with severe hemophilia A (306700) the deletion of 2 nucleotides (AA) resulting in a frameshift downstream from codon 2136 in exon 23.
Antonarakis et al. (1995) stated that this mutation had been reported in 10 patients with less than 1 to 7% factor VIII activity and severe to mild hemophilia A (306700). The mutation 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 was reported by Higuchi et al. (1991), Naylor et al. (1993), Diamond et al. (1992); and Jonsdottir et al. (1992). Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated arg2169-to-his (R2169H).
Antonarakis et al. (1995) reported this mutation in a patient with 3% factor VIII activity, 5.6% factor VIII antigen, and moderate hemophilia A (306700). The mutation was caused by a CCA-to-CAA transversion at codon 2153 in exon 23 of the C1 domain, resulting in glutamine for proline-2153.
Jonsdottir et al. (1992) found this mutation in a patient with 6% factor VIII activity and mild hemophilia A (306700). The mutation was caused by an ACT-to-ATT transition at codon 2154 in exon 23 of the C1 domain, resulting in isoleucine for threonine-2154.
Antonarakis et al. (1995) stated that this mutation had been reported in 12 patients with 6 to 26% factor VIII activity, less than 5 to 15.7% factor VIII antigen, and mild hemophilia A (306700). The mutation 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 mutation was reported by Higuchi et al. (1991), McGinniss et al. (1993); Diamond et al. (1992); and Jonsdottir et al. (1992).
Antonarakis et al. (1995) reported this mutation in a patient with 12% factor VIII activity, 4.8% factor VIII antigen, and mild hemophilia A (306700). The mutation was caused by a CGC-to-CTC transversion at codon 2159 in exon 23 of the C1 domain, resulting in leucine for arginine-2159.
Antonarakis et al. (1995) reported this mutation in a patient with 22% factor VIII activity, 11.9% factor VIII antigen, and mild hemophilia A (306700). The mutation 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.
Antonarakis et al. (1995) reported this mutation in 2 patients with 5% factor VIII antigen and moderate hemophilia A (306700). The mutation was caused by a CGC-to-CAC transition at codon 2163 in exon 23 of the C1 domain, resulting in histidine for arginine-2163.
Reiner et al. (1992) found this mutation in a patient with 1% factor VIII activity, less than 10% factor VIII antigen, and moderate hemophilia A (306700). The mutation 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.
Lin et al. (1993) found this mutation in a patient with 1% factor VIII activity and moderate hemophilia A (306700). The mutation was caused by a GCT-to-CCT transversion at codon 2192 in exon 24 of the C2 domain, resulting in proline for alanine-2192.
In 3 patients with less than 1% factor VIII activity and severe-to-moderate hemophilia A (306700), 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.
Millar et al. (1991) found this mutation in a patient with 3% factor VIII activity, 2.5% factor VIII antigen, and moderate hemophilia A (306700). The mutation was caused by a CGA-to-CTA transversion at codon 2209 in exon 24 of the C2 domain, resulting in leucine for arginine-2209.
Antonarakis et al. (1995) reported this mutation in a patient with less than 1% factor VIII activity and severe hemophilia A (306700). The mutation was caused by a CGA-to-GGA transversion at codon 2209 in exon 24 of the C2 domain, resulting in glycine for arginine-2209.
Antonarakis et al. (1995) reported in 1 patient with severe hemophilia A (306700) the deletion of 1 nucleotide (G) resulting in a frameshift downstream from codon 2214 in exon 24.
Naylor et al. (1991) and Diamond et al. (1992) found this mutation in 2 patients with 3% factor VIII activity, moderate hemophilia A (306700), and inhibitors in 1 out of the 2. The mutation was caused by a TGG-to-TGT transversion at codon 2229 in exon 25 of the C2 domain, resulting in cysteine for tryptophan-2229. Including the 19-amino acid signal peptide of the F8 gene (Vehar et al., 1984), this mutation is designated trp2248-to-cys (W2248C).
Antonarakis et al. (1995) reported this mutation in a patient with 4.5% factor VIII activity, 1.1% factor VIII antigen, and moderate hemophilia A (306700). The mutation was caused by a CAG-to-CGG transition at codon 2246 in exon 25 of the C2 domain, resulting in arginine for glutamine-2246.
Lin et al. (1993) identified in 1 patient with severe hemophilia A (306700) the deletion of 2 nucleotides (AG) resulting in a frameshift downstream from glutamine-2246 in exon 25.
In 1 patient with hemophilia A (306700), Antonarakis et al. (1995) reported the mutation of CAG-to-TAG at codon 2270 in exon 25, resulting in a stop codon.
Antonarakis et al. (1995) reported in 1 patient with severe hemophilia A (306700) the deletion of 5 nucleotides (AAATC) resulting in a frameshift downstream from codon 2285-86 or 87 in exon 26.
Higuchi et al. (1991) found this mutation in a patient with 7.5% factor VIII activity and mild hemophilia A (306700). The mutation 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.
Higuchi et al. (1991) and Reiner et al. (1992) found this mutation in 2 patients with less than 1% factor VIII activity, less than 10% factor VIII antigen, and severe hemophilia A (306700). The mutation 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.
Antonarakis et al. (1995) reported this mutation in a patient with mild hemophilia A (306700). The mutation 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.
In a patient with severe hemophilia A (306700) (patient H238) and factor VIII inhibitors, Millar et al. (1990) found a deletion of exons 1-6 of the factor VIII gene.
In a patient with severe hemophilia A (306700) (patient TWN11) and factor VIII inhibitors, Lin et al. (1993) found a deletion of exons 2-4 of the factor VIII gene.
In a patient with severe hemophilia A (306700) (patient H151), Millar et al. (1990) found a deletion of exons 3-5 of the factor VIII gene.
In a patient with severe hemophilia A (306700) (patient TWN27) and factor VIII inhibitors, Lin et al. (1993) found a deletion of exons 4-10 of the factor VIII gene.
In a patient with severe hemophilia A (306700) (patient H571) and factor VIII inhibitors, Millar et al. (1990) found a deletion of exons 5-13 of the factor VIII gene.
In a patient with severe hemophilia A (306700) (patient 149), Krepelova et al. (1992) found a deletion of exon 10 of the factor VIII gene.
In a patient with severe hemophilia A (306700) (patient H229) and factor VIII inhibitors, Millar et al. (1990) found a deletion of exons 14-21 of the factor VIII gene.
In a patient with severe hemophilia A (306700) (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).
Antonarakis et al. (1995) reported 3 patients with severe hemophilia A (306700) who had a deletion of exons 15-22 of the factor VIII gene.
In a patient with severe hemophilia A (306700) (patient HDX3) and factor VIII inhibitors, Figueiredo et al. (1992) found a deletion of exons 16-26 of the factor VIII gene.
In a patient with severe hemophilia A (306700) (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.
In a patient with severe hemophilia A (306700) (patient HD10), Schwaab et al. (1993) found a deletion of exon 16 of the factor VIII gene.
In a patient with severe hemophilia A (306700) (patient H58) and factor VIII inhibitors, Millar et al. (1990) found a deletion of exons 19-21 of the factor VIII gene.
In a patient with severe hemophilia A (306700) (patient HA711), Lavergne et al. (1992) found a deletion of exons 23-24 of the factor VIII gene.
In a patient with severe hemophilia A (306700) (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).
Favier et al. (2000) described a 14-month-old girl with severe hemophilia A (306700). 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.
In 2 brothers with severe hemophilia A (306700), 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 A1 domain that is conserved in the sequences of the murine, canine, and swine factor 8 genes. A maternal first cousin showed factor VIII deficiency and bleeding, but was found instead to have von Willebrand disease type 2N (see 613554) due to compound heterozygous mutations in the VWF gene (613160.0035 and 613160.0036).
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 (306700) 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.
Sukarova et al. (2001) described a family with a severe form of hemophilia A (306700) 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.
In 2 unrelated probands with mild hemophilia A (HEMA; 306700), Jourdy et al. (2018) identified an intronic deletion (c.2113+461_2113+473del, NM_000132.3) in intron 13 of the F8 gene. Transcription analysis of patient cells showed an aberrant transcript resulting from this deletion; it caused the insertion of a 122-bp intronic fragment (c.2113_2114ins2113+477_2113+598) at the exon 13-14 junction. This out-of-frame insertion was predicted to result in a truncated protein (Gly705AspfsTer37). DNA sequencing analysis showed that the included pseudoexon corresponds to an antisense AluY element, and that the deletion removed a part of the poly(T)-tail from the right arm of AluY. The findings suggested aberrant exonization of the AluY element that likely resulted from decreased binding of the cryptic exon silencer HNRNPC (164020). Disruption of or siRNA-mediated knockdown of HNRNPC in HeLa cells reproduced the effect of the deletion. Screening of 992 unrelated French families with mild hemophilia A found a deletion in the poly(T)-tail of AluY in intron 13 in 6.1% of families, although these resulted from several different intronic deletions in this region, suggesting a recurring molecular mechanism. Haplotype analysis suggested a founder effect for c.2113+461_2113+473del. The patients also carried a normal F8 transcript in addition to the aberrant transcript, explaining the mild phenotype.
In 7 individuals from 2 Italian families with thrombophilia due to factor VIII defect (THPH13; 301071), Simioni et al. (2021) identified a 23.4-kb tandem duplication in the F8 gene, including the promoter, exon 1, and part of intron 1. The mutation was hemizygous in affected males and heterozygous in affected females. The mutation was found by a combination of linkage analysis, MLPA analysis, whole-genome sequencing, and Sanger sequencing. The mutation segregated with disease in both families. The variant was not present in the 1000 Genomes Project database or in 103 control individuals. F8 mRNA was increased in patient lymphocytes. Increased transcriptional activity of fragments of the duplicated region was demonstrated via luciferase assay. The authors designated this mutation 'FVIII Padua.'
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. [PubMed: 2387581] [Full Text: https://doi.org/10.1016/0888-7543(90)90188-z]
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. [PubMed: 8497853]
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. [PubMed: 1569180] [Full Text: https://doi.org/10.1172/JCI115725]
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. [PubMed: 1594597] [Full Text: https://doi.org/10.1073/pnas.89.11.4933]
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. [PubMed: 1569181] [Full Text: https://doi.org/10.1172/JCI115726]
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 325: 1407-1409, 1985. Note: Originally Volume I. [PubMed: 2861360] [Full Text: https://doi.org/10.1016/s0140-6736(85)91842-2]
Antonarakis, S. E., Kazazian, H. H., Tuddenham, G. D. Molecular etiology of factor VIII deficiency in hemophilia A. Hum. Mutat. 5: 1-22, 1995. [PubMed: 7728145] [Full Text: https://doi.org/10.1002/humu.1380050102]
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. [PubMed: 7662970]
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. [PubMed: 2993888] [Full Text: https://doi.org/10.1056/NEJM198510033131402]
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. [PubMed: 2104766]
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. [PubMed: 2498882] [Full Text: https://doi.org/10.1073/pnas.86.11.4277]
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. [PubMed: 2501212] [Full Text: https://doi.org/10.1016/0888-7543(89)90269-3]
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. [PubMed: 2835307] [Full Text: https://doi.org/10.1007/BF00291718]
Barrow, E. M. S., Graham, J. B. Factor VIII. (Letter) Lancet 301: 1312-1313, 1973. Note: Originally Volume I. [PubMed: 4126092] [Full Text: https://doi.org/10.1016/s0140-6736(73)91319-6]
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. [PubMed: 8576960] [Full Text: https://doi.org/10.1007/BF00163204]
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. [PubMed: 8644728]
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-transcribed factor VIII mRNA. Hum. Genet. 85: 655-658, 1990. [PubMed: 2121641] [Full Text: https://doi.org/10.1007/BF00193593]
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. [PubMed: 2493803] [Full Text: https://doi.org/10.1111/j.1365-2141.1989.tb04266.x]
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. [PubMed: 8069313] [Full Text: https://doi.org/10.1093/hmg/3.4.651]
Bird, A. P. DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Res. 8: 1499-1504, 1980. [PubMed: 6253938] [Full Text: https://doi.org/10.1093/nar/8.7.1499]
Bloom, A. L., Peake, I. R. Molecular genetics of factor VIII and its disorders. Semin. Hemat. 14: 319-339, 1977. [PubMed: 327558]
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.
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. [PubMed: 8968748] [Full Text: https://doi.org/10.1093/hmg/5.12.1945]
Brinkhous, K. M., Graham, J. B. Hemophilia in the female dog. Science 111: 723-724, 1950. [PubMed: 15431070] [Full Text: https://doi.org/10.1126/science.111.2896.723]
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. [PubMed: 1975557] [Full Text: https://doi.org/10.1007/BF00206748]
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. (Abstract) Ric. Clin. Lab. 16: 227 only, 1986.
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. [PubMed: 2105106]
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. [PubMed: 2510835]
Cooper, D. N., Youssoufian, H. The CpG dinucleotide and human genetic disease. Hum. Genet. 78: 151-155, 1988. [PubMed: 3338800] [Full Text: https://doi.org/10.1007/BF00278187]
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. [PubMed: 4213756] [Full Text: https://doi.org/10.1172/JCI107853]
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. [PubMed: 11857744] [Full Text: https://doi.org/10.1002/humu.10056]
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. [PubMed: 8054459] [Full Text: https://doi.org/10.1097/00001721-199404000-00016]
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. [PubMed: 1301932] [Full Text: https://doi.org/10.1002/humu.1380010312]
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.
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. [PubMed: 1662412] [Full Text: https://doi.org/10.1126/science.1662412]
Eckhardt, C. L., van Velzen, A. S., Peters, M., Astermark, J., Brons, P. P., Castaman, G., Cnossen, M. H., Dors, N., Escuriola-Ettingshausen, C., Hamulyak, K., Hart, D. P., Hay, C. R. M., and 33 others. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A. Blood 122: 1954-1962, 2013. Note: Erratum: Blood 123: 3056 only, 2014. [PubMed: 23926300] [Full Text: https://doi.org/10.1182/blood-2013-02-483263]
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. [PubMed: 1639429] [Full Text: https://doi.org/10.1016/0888-7543(92)90189-y]
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. [PubMed: 11110718]
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. [PubMed: 6818542] [Full Text: https://doi.org/10.1073/pnas.79.23.7200]
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. [PubMed: 1559571] [Full Text: https://doi.org/10.1111/j.1600-0609.1992.tb00587.x]
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. [PubMed: 1609806]
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. [PubMed: 12884004] [Full Text: https://doi.org/10.1007/s00439-003-0986-5]
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. [PubMed: 2986011] [Full Text: https://doi.org/10.1038/314738a0]
Gitschier, J., Wood, W. I., Goralka, T. M., Wion, K. L., Chen, E. Y., Eaton, D. H., Vehar, G. A., Capon, D. J., Lawn, R. M. Characterization of the human factor VIII gene. Nature 312: 326-330, 1984. [PubMed: 6438525] [Full Text: https://doi.org/10.1038/312326a0]
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 232: 1415-1416, 1986. [PubMed: 3012775] [Full Text: https://doi.org/10.1126/science.3012775]
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. [PubMed: 2987704] [Full Text: https://doi.org/10.1038/315427a0]
Gitschier, J. Maternal duplication associated with gene deletion in sporadic hemophilia. Am. J. Hum. Genet. 43: 274-279, 1988. [PubMed: 2901224]
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. [PubMed: 2994779]
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. [PubMed: 56653] [Full Text: https://doi.org/10.1016/s0140-6736(76)90485-2]
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. [PubMed: 18691168] [Full Text: https://doi.org/10.1111/j.1365-2141.2008.07310.x]
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. [PubMed: 1768766] [Full Text: https://doi.org/10.1097/00001721-199108000-00007]
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. [PubMed: 2887317] [Full Text: https://doi.org/10.1111/j.1399-0004.1987.tb03316.x]
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. [PubMed: 16786531] [Full Text: https://doi.org/10.1002/humu.20345]
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. [PubMed: 1924291] [Full Text: https://doi.org/10.1073/pnas.88.19.8307]
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. [PubMed: 1908096] [Full Text: https://doi.org/10.1073/pnas.88.16.7405]
Higuchi, M., Kochhan, L., Olek, K. A somatic mosaic for haemophilia A detected at the DNA level. Molec. Biol. Med. 5: 23-27, 1988. [PubMed: 3131627]
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. [PubMed: 2473810]
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. [PubMed: 2105906] [Full Text: https://doi.org/10.1016/0888-7543(90)90448-4]
Hoyer, L. W. The factor VIII complex: structure and function. Blood 58: 1-13, 1981. [PubMed: 6165414]
Hoyer, L. W. Hemophilia A. New Eng. J. Med. 330: 38-45, 1994. [PubMed: 8259143] [Full Text: https://doi.org/10.1056/NEJM199401063300108]
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. [PubMed: 2495245] [Full Text: https://doi.org/10.1007/BF00283686]
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. [PubMed: 1688823] [Full Text: https://doi.org/10.1007/BF00208947]
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. [PubMed: 1159083] [Full Text: https://doi.org/10.1172/JCI108140]
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. [PubMed: 2882794]
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. [PubMed: 8052958]
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. [PubMed: 1301960] [Full Text: https://doi.org/10.1002/humu.1380010610]
Jourdy, Y., Janin, A., Fretigny, M., Lienhart, A., Negrier, C., Bozon, D., Vinciguerra, C. Recurrent F8 intronic deletion found in mild hemophilia A causes Alu exonization. Am. J. Hum. Genet. 102: 199-206, 2018. [PubMed: 29357978] [Full Text: https://doi.org/10.1016/j.ajhg.2017.12.010]
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. [PubMed: 2831458] [Full Text: https://doi.org/10.1038/332164a0]
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. [PubMed: 2589319]
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. [PubMed: 1303175] [Full Text: https://doi.org/10.1093/hmg/1.3.179]
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. [PubMed: 2107542] [Full Text: https://doi.org/10.1073/pnas.87.6.2092]
Krepelova, A., Vorlova, Z., Zavadil, J., Brdicka, R. Factor VIII gene deletions in haemophilia A patients in Czechoslovakia. Brit. J. Haemat. 81: 271-276, 1992. [PubMed: 1643024] [Full Text: https://doi.org/10.1111/j.1365-2141.1992.tb08219.x]
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. [PubMed: 8275087] [Full Text: https://doi.org/10.1038/ng1193-236]
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. Franc. Hemat. 34: 85-91, 1992. [PubMed: 1523102]
Lawn, R. M. The molecular genetics of hemophilia: blood clotting factors VIII and IX. Cell 42: 405-406, 1985. [PubMed: 2992799] [Full Text: https://doi.org/10.1016/0092-8674(85)90094-7]
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. [PubMed: 3122181] [Full Text: https://doi.org/10.1093/nar/15.23.9797]
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. [PubMed: 2110545] [Full Text: https://doi.org/10.1016/0888-7543(90)90512-s]
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. [PubMed: 2104741]
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.
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. [PubMed: 8307558]
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. [PubMed: 12242334] [Full Text: https://doi.org/10.1073/pnas.192219599]
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. [PubMed: 4626584] [Full Text: https://doi.org/10.1172/JCI107022]
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. [PubMed: 12406074] [Full Text: https://doi.org/10.1046/j.1365-2141.2002.03819.x]
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. [PubMed: 8449505] [Full Text: https://doi.org/10.1006/geno.1993.1073]
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. Note: Erratum: Genomics 16: 792 only, 1993. [PubMed: 8486358] [Full Text: https://doi.org/10.1006/geno.1993.1134]
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. [PubMed: 2907841]
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. [PubMed: 2125022] [Full Text: https://doi.org/10.1007/BF00197709]
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. [PubMed: 1840568] [Full Text: https://doi.org/10.1007/BF00209022]
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). (Abstract) Am. J. Hum. Genet. 39: A126, 1986.
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. [PubMed: 2159433] [Full Text: https://doi.org/10.1016/0888-7543(90)90526-z]
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. [PubMed: 4000972] [Full Text: https://doi.org/10.1093/nar/13.9.3131]
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. [PubMed: 2987873] [Full Text: https://doi.org/10.1093/nar/13.9.3111]
Nafa, K., Baudis, 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. [PubMed: 1301194] [Full Text: https://doi.org/10.1002/humu.1380010114]
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. [PubMed: 1969840] [Full Text: https://doi.org/10.1007/BF00195808]
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. [PubMed: 1671991] [Full Text: https://doi.org/10.1016/0140-6736(91)92450-g]
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. [PubMed: 1357455] [Full Text: https://doi.org/10.1016/0140-6736(92)93080-7]
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. [PubMed: 8490618] [Full Text: https://doi.org/10.1093/hmg/2.1.11]
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. [PubMed: 8281136] [Full Text: https://doi.org/10.1093/hmg/2.11.1773]
Nilsson, I. M., Blomback, M., Ramgren, O. Investigations on hemophilia A and B carriers. Bibl. Haemat. 26: 26-29, 1966. [PubMed: 5955559]
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. [PubMed: 2109644]
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. [PubMed: 2986139] [Full Text: https://doi.org/10.1073/pnas.82.9.2824]
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. [PubMed: 11023529]
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. [PubMed: 2565080]
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. [PubMed: 3482420] [Full Text: https://doi.org/10.1016/0888-7543(87)90028-0]
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. [PubMed: 1979502]
Paynton, C., Sarkar, G., Sommer, S. S. Identification of mutations in two families with sporadic hemophilia A. Hum. Genet. 87: 397-400, 1991. [PubMed: 1908817] [Full Text: https://doi.org/10.1007/BF00197155]
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. [PubMed: 2865465] [Full Text: https://doi.org/10.1016/s0140-6736(85)90542-2]
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. [PubMed: 8322269]
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. [PubMed: 1924290] [Full Text: https://doi.org/10.1073/pnas.88.19.8302]
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. [PubMed: 10586887] [Full Text: https://doi.org/10.1038/46601]
Ratnoff, O. D., Bennett, B. The genetics of hereditary disorders of blood coagulation. Science 179: 1291-1298, 1973. [PubMed: 4568863] [Full Text: https://doi.org/10.1126/science.179.4080.1291]
Ratnoff, O. D. Antihemophilic factor (factor VIII). Ann. Intern. Med. 88: 403-409, 1978. [PubMed: 343683] [Full Text: https://doi.org/10.7326/0003-4819-88-3-403]
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. [PubMed: 1412186] [Full Text: https://doi.org/10.1016/0049-3848(92)90159-8]
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. [PubMed: 1349567] [Full Text: https://doi.org/10.1007/BF00207049]
Roberts, D. F. The genetic basis of variation in factor VIII levels among haemophiliacs. J. Med. Genet. 8: 136-139, 1971. [PubMed: 5096534] [Full Text: https://doi.org/10.1136/jmg.8.2.136]
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. [PubMed: 7981669] [Full Text: https://doi.org/10.1093/hmg/3.7.1035]
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. [PubMed: 2999980] [Full Text: https://doi.org/10.1126/science.2999980]
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. [PubMed: 18217193] [Full Text: https://doi.org/10.1007/s10038-007-0238-y]
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. Haemost. 74: 1402-1406, 1995. [PubMed: 8772209]
Schwaab, R., Oldenburg, J., Tuddenham, E. G. D., Brackmann, H. H., Olek, K. Mutations in haemophilia A. Brit. J. Haemat. 83: 450-458, 1993. [PubMed: 8485051] [Full Text: https://doi.org/10.1111/j.1365-2141.1993.tb04670.x]
Shen, W., Gu, Y., Zhu, R., Zhang, L., Zhang, J., Ying, C. Copy number variations of the F8 gene are associated with venous thromboembolism. Blood Cells Molec. Dis. 50: 259-262, 2013. [PubMed: 23403259] [Full Text: https://doi.org/10.1016/j.bcmd.2013.01.004]
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. [PubMed: 2506948]
Simioni, P., Cagnin, S., Sartorello, F., Sales, G., Pagani, L., Bulato, C., Gavasso, S., Nuzzo, F., Chemello, F., Radu, C. M., Tormene, D., Spiezia, L., Hackeng, T. M., Campello, E., Castoldi, E. Partial F8 gene duplication (factor VIII Padua) associated with high factor VIII levels and familial thrombophilia. Blood 137: 2383-2393, 2021. [PubMed: 33275657] [Full Text: https://doi.org/10.1182/blood.2020008168]
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. [PubMed: 11713379] [Full Text: https://doi.org/10.1159/000046602]
Summers, R. J., Meeks, S. L., Healey, J. F., Brown, H. C., Parker, E. T., Kempton, C. L., Doering, C. B., Lollar, P. Factor VIII A3 domain substitution N1922S results in hemophilia A due to domain-specific misfolding and hyposecretion of functional protein. Blood 117: 3190-3198, 2011. [PubMed: 21217077] [Full Text: https://doi.org/10.1182/blood-2010-09-307074]
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. [PubMed: 3013509] [Full Text: https://doi.org/10.1159/000132255]
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. [PubMed: 6438528] [Full Text: https://doi.org/10.1038/312342a0]
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. [PubMed: 2106480] [Full Text: https://doi.org/10.1016/0888-7543(90)90569-g]
Tuddenham, E. G. D., Cooper, D. N., Gitschier, J., Higuchi, M., Hoyer, L. W., Yoshioka, A., Peake, I. R., Schwaab, R., Olek, K., Kazazian, H. H., Lavergne, J.-M., Giannelli, F., Antonarakis, S. E. Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene. Nucleic Acids Res. 19: 4821-4833, 1991. [PubMed: 1923751] [Full Text: https://doi.org/10.1093/nar/19.18.4821]
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. [PubMed: 6783066] [Full Text: https://doi.org/10.1111/j.1365-2141.1981.tb02691.x]
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. [PubMed: 12351418] [Full Text: https://doi.org/10.1182/blood-2002-01-0277]
Vehar, G. A., Keyt, B., Eaton, D., Rodriguez, H., O'Brien, D. P., Rotblat, F., Oppermann, H., Keck, R., Wood, W. I., Harkins, R. N., Tuddenham, E. G. D., Lawn, R. M., Capon, D. J. Structure of human factor VIII. Nature 312: 337-342, 1984. [PubMed: 6438527] [Full Text: https://doi.org/10.1038/312337a0]
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. Note: Erratum: New Eng. J. Med. 361: 544 only, 2009. [PubMed: 19369668] [Full Text: https://doi.org/10.1056/NEJMoa075760]
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. [PubMed: 2567219]
Wion, K. L., Kelly, D., Summerfield, J. A., Tuddenham, E. G., Lawn, R. M. Distribution of factor VIII mRNA and antigen in human liver and other tissues. Nature 317: 726-729, 1985. [PubMed: 3932885] [Full Text: https://doi.org/10.1038/317726a0]
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. [PubMed: 6438526] [Full Text: https://doi.org/10.1038/312330a0]
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. [PubMed: 2497061] [Full Text: https://doi.org/10.1016/0888-7543(89)90332-7]
Woolf, L. I. Gene expression in heterozygotes. Nature 194: 609-610, 1962. [PubMed: 14008280] [Full Text: https://doi.org/10.1038/194609a0]
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. [PubMed: 9042915]
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. [PubMed: 3035554] [Full Text: https://doi.org/10.1073/pnas.84.11.3772]
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. [PubMed: 2833855]
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.
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. [PubMed: 3139545] [Full Text: https://doi.org/10.1007/BF00702857]
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. [PubMed: 3097553] [Full Text: https://doi.org/10.1038/324380a0]
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. [PubMed: 2835904]
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. [PubMed: 5751674]