Coagulation Factor VIII

Alternative Names

  • F8
  • Factor VIII
  • Coagulation Factor VIIIC, Procoagulant Component
  • F8C

Associated Diseases

Hemophilia A
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OMIM Number

300841

NCBI Gene ID

2157

Uniprot ID

P00451

Length

8,040,896 bases

No. of Exons

27

No. of isoforms

2

Protein Name

Coagulation factor VIII

Molecular Mass

267009 Da

Amino Acid Count

2351

Genomic Location

chrX:148,000,000-156,040,895

Gene Map Locus
Xq28

Description

This gene encodes coagulation factor VIII, which participates in the intrinsic pathway of blood coagulation; factor VIII is a cofactor for factor IXa which, in the presence of Ca+2 and phospholipids, converts factor X to the activated form Xa. This gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein, isoform a, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events. Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of the phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity. Defects in this gene results in hemophilia A, a common recessive X-linked coagulation disorder. [FromRefSeq]

Epidemiology in the Arab World

View Map
Variant NameCountryGenomic LocationClinvar Clinical SignificanceCTGA Clinical Significance Condition(s)HGVS ExpressionsdbSNPClinvar
NM_000132.3:c.104A>GLebanonNC_000023.11:g.155022449T>CPathogenicLikely PathogenicHemophilia ANG_011403.1:g.5275A>G; NM_000132.3:c.104A>G; NP_000123.1:p.Tyr35Cys13785247610352
NM_000132.3:c.1444-3C>GLebanonNC_000023.11:g.154961171G>CLikely PathogenicLikely PathogenicHemophilia ANG_011403.1:g.66553C>G; NM_000132.3:c.1444-3C>G; NP_000123.1:p.?1603435027811361
NM_000132.3:c.1445T>GLebanonNC_000023.11:g.154961167A>CLikely PathogenicHemophilia ANG_011403.1:g.66557T>G; NM_000132.3:c.1445T>G; NP_000123.1:p.Ile482Ser
NM_000132.3:c.1654T>CLebanonNC_000023.11:g.154957055A>GLikely PathogenicLikely PathogenicHemophilia ANG_011403.1:g.70669T>C; NM_000132.3:c.1654T>C; NP_000123.1:p.Tyr552His1603434863627012
NM_000132.3:c.2040_2043delLebanonNC_000023.11:g.154947768_154947771delLikely PathogenicHemophilia ANG_011403.1:g.79953_79956del; NM_000132.3:c.2040_2043del; NP_000123.1:p.Met681SerfsTer40
NM_000132.3:c.207_208delLebanonNC_000023.11:g.154999537_154999538delLikely PathogenicHemophilia ANG_011403.1:g.28187_28188del; NM_000132.3:c.207_208del; NP_000123.1:p.Phe70CysfsTer121338553567
NM_000132.3:c.277C>TLebanonNC_000023.11:g.154997084G>ALikely PathogenicHemophilia ANG_011403.1:g.30640C>T; NM_000132.3:c.277C>T; NP_000123.1:p.Pro93Ser
NM_000132.3:c.2830_2831delLebanonNC_000023.11:g.154930962_154930963delLikely PathogenicHemophilia ANG_011403.1:g.96764_96765del; NM_000132.3:c.2830_2831del; NP_000123.1:p.Lys944ValfsTer6
NM_000132.3:c.3301G>TLebanonNC_000023.11:g.154930489C>ALikely PathogenicHemophilia ANG_011403.1:g.97235G>T; NM_000132.3:c.3301G>T; NP_000123.1:p.Glu1101Ter782629200
NM_000132.3:c.4460delLebanonNC_000023.11:g.154929332delLikely PathogenicHemophilia ANG_011403.1:g.98394del; NM_000132.3:c.4460del; NP_000123.1:p.Asn1487IlefsTer80
NM_000132.3:c.5012G>ALebanonNC_000023.11:g.154928778C>TUncertain SignificanceLikely PathogenicHemophilia ANG_011403.1:g.98946G>A; NM_000132.3:c.5012G>A; NP_000123.1:p.Arg1671His782166477804139
NM_000132.3:c.5252A>GLebanonNC_000023.11:g.154906541T>CLikely PathogenicHemophilia ANG_011403.1:g.121183A>G; NM_000132.3:c.5252A>G; NP_000123.1:p.Lys1751Arg1328899797
NM_000132.3:c.601G>ALebanonNC_000023.11:g.154992936C>TLikely PathogenicLikely PathogenicHemophilia ANG_011403.1:g.34788G>A; NM_000132.3:c.601G>A; NP_000123.1:p.Gly201Arg1229954426811081
NM_000132.3:c.602-3C>ALebanonNC_000023.11:g.154987308G>TLikely PathogenicHemophilia ANG_011403.1:g.40416C>A; NM_000132.3:c.602-3C>A
NM_000132.3:c.6407G>ALebanonNC_000023.11:g.154896099C>TLikely PathogenicHemophilia ANG_011403.1:g.131625G>A; NM_000132.3:c.6407G>A; NP_000123.1:p.Gly2136Glu
NM_000132.3:c.6563G>ALebanonNC_000023.11:g.154863094C>TLikely PathogenicHemophilia ANG_011403.1:g.164630G>A; NM_000132.3:c.6563G>A; NP_000123.1:p.Cys2188Tyr1278160877
NM_000132.3:c.679T>GLebanonNC_000023.11:g.154984795A>CLikely PathogenicHemophilia ANG_011403.1:g.42929T>G; NM_000132.3:c.679T>G; NP_000123.1:p.Trp227Gly
NM_000132.3:c.6858_6868delLebanonNC_000023.11:g.154860464_154860474delLikely PathogenicHemophilia ANG_011403.1:g.167250_167260del; NM_000132.3:c.6858_6868del; NP_000123.1:p.Asp2286GlufsTer95
NM_000132.3:c.6907C>TLebanonNC_000023.11:g.154837746G>ALikely PathogenicHemophilia ANG_011403.1:g.189978C>T; NM_000132.3:c.6907C>T; NP_000123.1:p.Gln2303Ter
NM_000132.3:c.763G>ALebanonNC_000023.11:g.154984711C>TLikely PathogenicHemophilia ANG_011403.1:g.43013G>A; NM_000132.3:c.763G>A; NP_000123.1:p.Gly255Ser

Other Reports

Algeria

In 1990, Nafa et al. investigated the allele frequencies of intragenic (intron 17 and intron 25) and extragenic (DXS15 and DXS52) F8 gene RFLPs in the Algerian population. Altogether, 287 X chromosomes (97 males and 95 females) were studied. A new allele (14 kb), called 1 DZ, was found in 3.1% of the chromosomes. Fifty-one families with hemophilia A were studied with the same probes (374 subjects). Of the females, 94% were informative for at least one intra- or extragenic RFLP. Two recombinations were found between DXS52 and F8, of which one occurred between the DXS15, DXS52 block and F8, indicating that the two anonymous loci are on the same side of the F8 gene. Only two obvious gene deletions were observed in 73 unrelated hemophiliacs: one was found in a patient with severe hemophilia A (patient H20) and encompassed exons 14-22 of the F8 gene (about 4.3 kb of cDNA and 36 kb of genomic DNA); the other removed the last exon (exon 26, representing 2 kb of cDNA). In a separate study, Nafa et al. (1992) found a novel mutation in a patient with 7% factor VIII activity and moderate hemophilia A. The mutation was caused by a CGA>CTA transversion at codon 1941 in exon 18 of the A3 domain, resulting in p.Arg1941Leu.

Lebanon

Djambas Khayat et al. (2008) studied the spectrum of F8 mutations in 79 Lebanese patients with mostly severe Hemophilia A. The study identified 17 missense, five nonsense and two splice site mutations, in addition to one large and seven small deletions in the patients. The large deletion involved the deletion of the entire exon 16. The novel mutations identified in this study are listed in the table above. The study also detected intron 22 inversions in 23 patients from 17 families and inversion of intron 1 in two brothers. 

Saudi Arabia

A study by Owaidah et al. (2009) evaluated the genotype-phenotype correlation in hemophilia A patients in Saudi Arabia. The study included 22 men affected with hemophilia A from 18 unrelated families. All, but two brothers, suffered severe hemophilia A with FVIII activity less than 1 IU/dl. The age range was 4-37 years and all patients experienced frequent bleeding episodes. Screening for F8 intron 22 inversions showed that 10 out of 22 cases were positive for this mutation. The remaining 12 patients were then screened for other mutations in the gene F8. The latter study unveiled six different mutations (5 missense and one deletion/insertion), of which one was a novel missense (p.R593P) and one was a novel deletion/insertion (a frameshift in codons 1226-1229). The two patients who suffered a mild phenotype were shown to have the missense mutation c.923C>T, while all other patients suffered a severe phenotype.

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