Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: F5
SNOMEDCT: 4320005;
Cytogenetic location: 1q24.2 Genomic coordinates (GRCh38) : 1:169,511,951-169,586,481 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q24.2 | {Budd-Chiari syndrome} | 600880 | Autosomal recessive | 3 |
| {Pregnancy loss, recurrent, susceptibility to, 1} | 614389 | Autosomal dominant | 3 | |
| {Stroke, ischemic, susceptibility to} | 601367 | Multifactorial | 3 | |
| {Thrombophilia, susceptibility to, due to factor V Leiden} | 188055 | Autosomal dominant | 3 | |
| Factor V deficiency | 227400 | Autosomal recessive | 3 | |
| Thrombophilia 2 due to activated protein C resistance | 188055 | Autosomal dominant | 3 |
The F5 gene encodes coagulation factor V, a large 330-kD plasma glycoprotein that circulates with little or no activity. Factor V is converted to the active form, factor Va, by thrombin (F2; 176930), which generates a heavy chain and a light chain held together by calcium ions. Activated factor V serves as an essential protein in the coagulation pathway and acts as a cofactor for the conversion of prothrombin to thrombin by factor Xa (F10; 613872). Factor Va is inactivated by activated protein C (PROC; 612283) (Kane and Davie, 1986; Cripe et al., 1992).
Kane et al. (1987) isolated clones corresponding to a portion of the F5 gene from a human hepatocellular carcinoma (Hep G2) cDNA library. The deduced 938-residue partial protein was composed of a 651-residue light chain and a 287-residue connecting region. The amino acid sequence of the light chain region was about 40% identical to the corresponding region of factor VIII (F8; 300841).
Jenny et al. (1987) isolated a complete cDNA for factor V from a human fetal liver cDNA library and determined that the deduced amino acid sequence consists of 2,224 residues including a 28-residue leader peptide. The triplicated A domain and duplicated C domain showed approximately 40% identity with the corresponding domains in factor VIII. Factor V contains 37 potential N-linked glycosylation sites, 25 of which are in the B domain, and a total of 19 cysteine residues.
Cripe et al. (1992) determined that the F5 gene contains 25 exons.
Riddell et al. (1987) and Wang et al. (1988) mapped the F5 gene to chromosome 1 by Southern hybridization to somatic cell hybrid DNAs. By in situ hybridization, F5 was regionalized to 1q21-q25. Dahlback et al. (1988) confirmed the assignment of F5 to human chromosome 1 by hybridization studies of a panel of human-rodent somatic cell hybrids, and mapped the rat gene to chromosome 13. Combining linkage data with the physical assignment of the F5 locus, McAlpine et al. (1989) concluded that F5 lies in the 1q23 band. They found that F5 and AT3 (107300) are closely linked, with F5 located distal to AT3.
Bauer (1994) reviewed the significance of the APC cofactor in the protein C anticoagulant pathway and illustrated it with a useful diagram.
Crystal Structure
Macedo-Ribeiro et al. (1999) determined 2 crystal structures of the C2 domain of human factor Va. The conserved beta-barrel framework provides a scaffold for 3 protruding loops, one of which adopts markedly different conformations in the 2 crystal forms. Macedo-Ribeiro et al. (1999) proposed a mechanism of calcium-independent, stereospecific binding of factors Va and VIIIa to phospholipid membranes on the basis of (1) immersion of hydrophobic residues at the apices of these loops in the apolar membrane core; (2) specific interactions with phosphatidylserine head groups in the groove enclosed by these loops; and (3) favorable electrostatic contacts of basic side chains with negatively charged membrane phosphate groups.
In discussing the good and bad aspects of factor V functionality and durability, Mann and Kalafatis (2003) referred to factor V as a combination of Dr. Jekyll and Mr. Hyde. Mutations resulting in the absence or dysfunction of activated factor V lead to hemorrhagic disease, whereas mutations resulting in excessive longevity of the active species are associated with thrombosis. Factor V is thus required for a good outcome (Dr. Jekyll) but also is a potential source of disaster (Mr. Hyde).
Factor V Deficiency
In a patient with mild bleeding due to factor V deficiency (227400), Guasch et al. (1998) identified a homozygous mutation in the F5 gene (612309.0004).
In a Korean woman with bleeding due to factor V deficiency, van Wijk et al. (2001) identified compound heterozygosity for 2 mutations in the F5 gene (612309.0006; 612309.0007).
Thrombophilia Due to Activated Protein C Resistance
In affected members of a family with thrombophilia due to APC resistance (THPH2; 188055), Bertina et al. (1994) identified a heterozygous R506Q mutation (612309.0001) in the F5 gene. This variant was referred to as factor V Leiden, named after the town in the Netherlands where Bertina et al. (1994) discovered the defect. Bertina et al. (1994) identified the same R506Q mutation in 56 of 64 patients with APC-resistant thrombosis from a larger cohort of 301 consecutive patients with a first episode of deep vein thrombosis. The mutation was homozygous in 6 patients.
Voorberg et al. (1994) found the R506Q mutation in 10 of 27 consecutive patients with recurrent thromboembolism.
Majerus (1994) quoted estimates that 2 to 4% of the Dutch population and 7% of the Swedish population carried the mutant R506Q allele. The high frequency of a single factor V mutation in diverse groups of people raised the question of whether positive selection pressure was involved in maintaining it in the population. Majerus (1994) suggested that a slight thrombotic tendency may confer some advantage in fetal implantation.
In a patient with thrombophilia due to APC resistance, Williamson et al. (1998) identified a heterozygous R306T mutation in the F5 gene (612309.0003). The mutation was also present in a first-degree relative with APC resistance.
In 2 Caucasian brothers with thrombophilia due to APC resistance, Mumford et al. (2003) identified compound heterozygosity for 2 mutations in the F5 gene: a missense mutation (I359T; 612309.0013) and a nonsense mutation (E119X; 612309.0014). Both brothers developed spontaneous venous thromboses in the second decade of life. One presented at the age of 14 years with thrombosis of the right femoral vein and inferior vena cava; an older brother had recurrent episodes of femoral vein thrombosis from the age of 18 years and was managed with long-term warfarin therapy. Heterozygous family members were asymptomatic.
Pseudohomozygosity for Factor V Leiden
Castaman et al. (1997) and Castoldi et al. (1998) described patients with thrombosis who were compound heterozygous for factor V Leiden and a factor V deficiency allele. The patients were referred to as having 'pseudohomozygosity' for factor V Leiden, since they presented with venous thromboembolic events. Although the resistance to APC is in the range of factor V Leiden homozygotes, genotyping demonstrated heterozygosity for the factor V Leiden mutation. Those with F5 null mutations showed only factor V Leiden molecules, and those with deficient mutations show decreased levels of F5 that were insufficient to protect against thrombosis.
Zehnder et al. (1999) identified a man with thrombophilia who was compound heterozygous for factor V Leiden and a null allele of the F5 gene (612309.0005). The patient had 50% of normal levels of F5, all of which was of the Leiden type; hence he was pseudohomozygous for factor V Leiden.
Among 7 families with 11 pseudohomozygotes and 45 relatives, Castaman et al. (1999) found that 16 relatives were heterozygous factor V Leiden carriers, 9 showed partial factor V deficiency, and 20 had no abnormalities. Deep vein thrombosis occurred in 4 of 11 (36.3%) pseudohomozygous patients, in 6 of 16 (37.4%) factor V Leiden carriers, and in 1 of 20 (5%) normal relatives. Castaman et al. (1999) concluded that pseudohomozygosity for APC resistance carries a significantly higher risk for venous thromboembolism in comparison to normal subjects, but probably not in comparison to heterozygous FV Leiden carriers.
Other Disease Associations
Faisel et al. (2004) analyzed the allele and genotype frequencies of 2 F5 polymorphisms, M385T, R485K, and the R506Q Leiden mutation in 133 Finnish women with preeclampsia (189800) and 112 controls. There were statistically significant differences in R485K allele (p = 0.003) and genotype (p = 0.03) frequencies between patients and controls. The A allele of R485K was overrepresented among the patients (12%) compared to the controls (4%), with an odds ratio (OR) of 2.8 (95% CI, 1.2-6.2) for combined A genotypes. Faisel et al. (2004) concluded that genetic variations in the factor V gene other than the Leiden mutation may play a role in disease susceptibility.
Hao et al. (2004) conducted a large-scale case-control study exploring the associations of 426 single-nucleotide polymorphisms (SNPs) with preterm delivery in 300 mothers with preterm delivery and 458 mothers with term deliveries. Twenty-five candidate genes were included in the final haplotype analysis, and there was a significant association between a F5 gene haplotype and preterm delivery.
Hayward et al. (1996) described an autosomal dominant bleeding disorder in a Quebec family that was associated with reduced to normal platelet counts, defective epinephrine aggregation, and multiple glycoprotein abnormalities. This disorder had been previously designated 'factor V (Quebec)' by Tracy et al. (1984) because of abnormalities in platelet factor V. However, Hayward et al. (1996, 1997) and Janeway et al. (1996) determined that, although platelet factor V was indeed deficient in this disorder, several other platelet alpha-granular proteins were also deficient. The findings indicated that this was not a primary defect of factor V, but rather a distinct entity, now referred to as the Quebec platelet disorder (601709).
Cui et al. (1996) found that approximately half of homozygous factor V-null mouse embryos died at embryonic days 9 to 10, possibly as a result of an abnormality in the yolk-sac vasculature. The remaining homozygous deficient mice progressed normally to term, but died from massive hemorrhage within 2 hours of birth. Considered together with the milder phenotypes generally associated with deficiencies of other clotting factors, the findings demonstrated the primary role of the common coagulation pathway and the absolute requirement for functional factor V for prothrombinase activity. The results also provided direct evidence for the existence of other critical hemostatic functions for thrombin in addition to fibrin clot formation, and identified a previously unrecognized role for the coagulation system in early mammalian development.
Cui et al. (2000) found that mice carrying the R504Q mutation, homologous to human factor V Leiden (R506Q), were viable and fertile and exhibited normal survival. Compared with wildtype mice, adult homozygous mice demonstrated a marked increase in spontaneous tissue fibrin deposition. On a mixed genetic background, homozygous mice developed disseminated intravascular thrombosis in the perinatal period, resulting in significant mortality shortly after birth. Cui et al. (2000) suggested that these results may explain the high degree of conservation of the R504/R506 activated protein C cleavage site within factor V among mammalian species.
This mutation is commonly referred to as 'factor V Leiden.'
Thrombophilia
In affected members of a family with thrombophilia due to APC resistance (188055), Bertina et al. (1994) identified a heterozygous 1691G-A transition in exon 10 of the F5 gene, resulting in an arg506-to-gln (R506Q) substitution. The R506Q substitution prevented inactivation of activated factor V by activated protein C (612283), resulting in a tendency to thrombosis. Of note, this family came to attention because of symptomatic protein C deficiency (176860). Bertina et al. (1994) identified the R506Q mutation in 56 of 64 patients with APC-resistant thrombosis from a larger cohort of 301 consecutive patients with a first episode of deep vein thrombosis. The mutation was homozygous in 6 patients.
Greengard et al. (1994) identified a heterozygous R506Q mutation in 8 patients with APC resistance; 2 were Ashkenazi Jews, 5 were Europeans of varying origins, and 1 was African American. Voorberg et al. (1994) found the R506Q mutation in 10 of 27 consecutive patients with recurrent thromboembolism.
Beauchamp et al. (1994) found the R506Q mutation in all affected members of 2 English families with inherited APC resistance associated with thrombosis. The molecular studies confirmed suspected homozygosity in 2 individuals. The mutation in heterozygous form was also found in approximately 3.5% of the normal population.
Among 14,916 apparently healthy men in the Physicians' Health Study, including 121 with deep venous thrombosis, Ridker et al. (1995) found that the R506Q mutation of the F5 gene was present in 25.8% of men over the age of 60 in whom primary venous thrombosis developed. There was no increased risk for secondary venous thrombosis. The presence of the mutation was not associated with an increased risk of myocardial infarction or stroke. In a follow-up study, of 77 study participants who had a first idiopathic venous thromboembolism, Ridker et al. (1995) found that factor V Leiden was associated with a 4- to 5-fold increased risk of recurrent thrombosis. The data raised the possibility that patients with idiopathic venous thromboembolism and factor V Leiden may require more prolonged anticoagulation to prevent recurrent disease compared to those without the mutation.
Among 7 families with 11 pseudohomozygotes and 45 relatives, Brenner et al. (1996) observed 2 patients with the HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome who were found to be heterozygous for the R506Q mutation. The HELLP syndrome is a severe presentation of preeclampsia (see 189800). The finding of the R506Q mutation suggested that the pathogenesis of HELLP syndrome may be associated with a thrombotic process.
In 50 patients with meningococcal disease and thrombotic complications, Westendorp et al. (1996) found no increase in prevalence of the factor V Leiden mutation.
De Bruijn et al. (1998) studied risk factors in cerebral venous sinus thrombosis in women. They found a clear and significant excess of both hereditary prothrombotic conditions, including factor V Leiden, and oral contraceptive use in 40 prospectively ascertained patients compared to 2,248 randomly sampled controls. The authors concluded that the presence of prothrombotic conditions like the factor V Leiden mutation and the use of oral contraceptives increase the risk of this rare condition in a multiplicative fashion.
Gerhardt et al. (2000) studied 119 women with a history of venous thromboembolism during pregnancy and the puerperium and 233 age-matched normal women. Among the women with a history of venous thromboembolism, a prevalence of factor V Leiden was 43.7%, as compared with 7.7% among the normal women (relative risk of venous thromboembolism, 9.3). The prevalence of the 20210G-A prothrombin mutation (176930.0009) was 16.9% in the thromboembolism group as compared with 1.3% in the control group. The frequency of both factor V Leiden and the 20210G-A prothrombin mutation was 9.3% in the thromboembolism group as compared with 0 in the control group (estimated OR, 107). Assuming an overall risk of 1 in 1,500 pregnancies, the risk of thrombosis among carriers of factor V Leiden was 0.2%, among carriers of the 20210G-A prothrombin mutation, 0.5%, and among carriers of both defects, 4.6%, as calculated in a multivariate analysis. Thus, the risk among women with both mutations was disproportionately higher than that among women with only 1 mutation.
In a population-based cohort study of 9,253 Danish adults, Juul et al. (2004) found that heterozygotes and homozygotes for factor V Leiden had 2.7 and 18 times higher risk for venous thromboembolism, respectively, than noncarriers. Absolute 10-year risks for thromboembolism among heterozygote and homozygote nonsmokers younger than age 40 years who were not overweight were 0.7% and 3%, respectively. The 10-year risks in heterozygotes and homozygotes older than age 60 years who smoked and were overweight were 10% and 51%, respectively.
Kemkes-Matthes et al. (2005) found that presence of a heterozygous or homozygous arg225-to-his (R225H) substitution in exon 8 of the protein Z gene (PROZ; 176895) was associated with a higher frequency of thromboembolic complications in patients carrying the factor V Leiden mutation, although plasma levels of protein Z were not different between those with or without the R225H substitution. In a study of 134 carriers of factor V Leiden, the R225H mutation was found in 11 (14.4%) of 76 patients with thromboembolic events and in only 3 (5.1%) of 58 patients who did not have thromboembolic events.
Stroke
In a comprehensive metaanalysis of 26 case-control studies including 4,588 white adult patients, Casas et al. (2004) found a statistically significant association between ischemic stroke (601367) and the R506Q substitution (OR, 1.33).
Budd-Chiari Syndrome
Mahmoud et al. (1997) reported the incidence of the factor V Leiden mutation in Budd-Chiari syndrome (600880) and portal vein thrombosis. The R506Q mutation was seen in 7 (23%) of 30 patients with Budd-Chiari syndrome (6 heterozygotes and 1 homozygote), 3 of whom had coexistent myeloproliferative disease. Only 1 (3%) of 32 patients with portal vein thrombosis was found to have the R506Q mutation. The mutation was found in 3 (6%) of the 54 controls, who had liver disease but no history of thrombophilia. Mahmoud et al. (1997) concluded that the R506Q mutation seems to be an important factor in the pathogenesis of Budd-Chiari syndrome but not of portal vein thrombosis.
Leebeek et al. (1998) described a 27-year-old woman, homozygous for factor V Leiden, who developed Budd-Chiari syndrome caused by hepatic vein thrombosis in association with portal and mesenteric vein thrombosis. Gurakan et al. (1999) described a child with Budd-Chiari syndrome who was homozygous for the factor V Leiden mutation. The authors noted that Budd-Chiari syndrome is rare in children.
Recurrent Pregnancy Loss
In a study of 67 women with a first episode of unexplained late fetal loss (fetal death after 20 weeks or more of gestation; 614389) and 232 women who had had 1 or more normal pregnancies with no late fetal loss, Martinelli et al. (2000) found that both factor V Leiden and a 20210G-A mutation in prothrombin (176930.0009) were associated with an approximate tripling of the risk of late fetal loss.
Evolution
Zivelin et al. (2006) estimated the age of the factor V Leiden mutation to be 21,340 years. Like the prothrombin 20210G-A mutation (176930.0009), the mutation occurred in whites toward the end of the last glaciation and their wide distribution in whites suggested selective evolutionary advantages. A selective disadvantage (i.e., thrombosis) is unlikely because until recent centuries humans did not live long enough to manifest a meaningful incidence of thrombosis. On the other hand, augmented hemostasis conceivably conferred a selective advantage by reducing mortality from postpartum hemorrhage, hemorrhagia associated with severe iron deficiency anemia, and posttraumatic bleeding. For example, Lindqvist et al. (1998) found that the amount of blood lost during labor was significantly smaller in heterozygotes with factor V Leiden than in women not carrying the mutation, and Lindqvist et al. (2001) found that profuse menstrual bleeding was significantly less common in factor V heterozygotes.
Among 122 pregnant women with preeclampsia or intrauterine growth retardation, Lindqvist et al. (1998) found a significantly reduced risk of intrapartum bleeding complications in the APC-resistant subgroup compared to non-APC-resistant subgroup, as indicated by reduced intrapartum blood loss and pre- and postpartum hemoglobin measurements. Lindqvist et al. (1998) speculated that the remarkably high prevalence of a potentially harmful factor V gene mutation in the general population may be the result of an evolutionary selection mechanism conferring such survival advantages as reduction in the risk of intrapartum bleeding.
Pseudohomozygosity for Factor V Leiden
Zehnder et al. (1999) identified a man with thrombophilia who was found to be compound heterozygous for factor V Leiden and a null allele of the F5 gene (612309.0005). The patient had 50% of normal levels of F5, all of which was of the Leiden type; hence he was 'pseudohomozygous' for factor V Leiden.
Digenic Inheritance
Koeleman et al. (1994) found that heterozygous carriers of both the R506Q and a mutation in the protein C gene were at higher risk of thrombosis than were patients with either defect alone.
Talmon et al. (1997) described retinal arterial occlusion in a child heterozygous for the factor V R506Q mutation and homozygous for thermolabile methylene tetrahydrofolate reductase (236250.0003). Thus, the coexistence of 2 mild hereditary thrombophilic states can result in severe thrombotic manifestations in young people. Although factor V Leiden had been associated clearly with venous thrombosis, most studies had failed to demonstrate an association between isolated factor V Leiden and arterial thrombosis.
De Stefano et al. (1999) examined the relative risk of recurrent deep venous thrombosis using a proportional-hazards model. The authors found that whereas patients who were heterozygous for factor V Leiden alone had a risk of recurrent deep venous thrombosis that was similar to that among patients who had neither mutation, patients who were heterozygous for both factor V Leiden and prothrombin 20210G-A (176930.0009) had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. Meinardi et al. (1999) described double homozygosity for factor V Leiden and prothrombin 20210G-A in a 34-year-old man with idiopathic venous thrombosis.
Meyer et al. (1999) described a method for simultaneously genotyping for factor V Leiden and the prothrombin 20210G-A variant by a multiplex PCR-SSCP assay on whole blood.
Population Studies
Majerus (1994) quoted estimates that 2 to 4% of the Dutch population and 7% of the Swedish population carried the factor V Leiden allele (R506Q; 612309.0001). The high frequency of a single factor V mutation in diverse groups of people raised the question of whether positive selection pressure was involved in maintaining it in the population. Majerus (1994) suggested that a slight thrombotic tendency may confer some advantage in fetal implantation.
In a population study in southern Germany, Braun et al. (1996) found that 7.8% of 180 unrelated individuals were heterozygous for the factor V Leiden mutation.
In a multiethnic survey of 602 Americans, Gregg et al. (1997) found that Hispanic Americans had the highest frequency of the Leiden mutant allele, 1.65%, while African Americans had a somewhat lower frequency, 0.87%. No instances of the Leiden mutation were found in 191 Asian Americans or 54 Native Americans tested. These results indicated that the Leiden mutation segregates in populations with significant Caucasian admixture and is rare in genetically distant non-European groups.
Gurgey and Mesci (1997) determined that the F5 Leiden allele has a frequency of 8% in the Turkish population.
Chan et al. (1998) found that the R506Q mutation was rare among Hong Kong Chinese, as it was not detected among 83 unrelated Hong Kong Chinese, 43 of whom had deep venous thromboses.
In 2 patients with deep vein thrombosis and 1 nonthrombotic individual, Chan et al. (1998) identified a 1090A-G sequence change in exon 7 of the F5 gene, resulting in an arg306-to-gly (R306G) substitution. Fresh blood samples available from 1 of them showed no resistance to activated protein C.
Liang et al. (1998) found that the mutant R306G protein retained susceptibility to cleavage by activated protein C. In contrast, the R306T substitution (612309.0003) conferred resistance to protein C cleavage. In Hong Kong, R306G was found in 4 of 89 (4.5%) healthy blood donors and 8 of 260 (3.1%) diabetic subjects. There was no statistically significant difference between these 2 figures and the incidence rate of 2 in 43 (4.7%) previously reported by Chan et al. (1998) in thrombotic patients. The data suggested that the R306G variant does not predispose to clinical thrombosis.
In a patient with thrombophilia due to APC resistance (188055), Williamson et al. (1998) identified a G-to-C transversion in the F5 gene, resulting in an arg306-to-thr (R306T) substitution. The mutation was also present in a first-degree relative with APC resistance. This was the first description of a mutation affecting the arg306 APC cleavage site, and the only mutation other than factor V Leiden (612309.0001) found in association with APC resistance. Discovered at Addenbrooke's Hospital in Cambridge, England, the variant was referred to as factor V Cambridge.
In a young girl with very mild bleeding symptoms and undetectable levels of plasma factor V antigen and activity (227400), Guasch et al. (1998) identified a homozygous 4-bp deletion in exon 13 of the F5 gene, resulting in a frameshift and premature protein termination. The truncated factor V molecule was predicted to lack part of the B domain and the complete light chain. However, no factor V heavy chain could be detected in the plasma of the patient or in the patient's platelets. This was the first reported mutation in the factor V gene that predicted a type I quantitative factor V deficiency. The patient presented at the age of 3 years with prolonged bleeding from a cut in her upper lip after trauma. The parents were consanguineous, and each had a plasma level of factor V activity of about 50% of normal.
Zehnder et al. (1999) identified a man with thrombophilia (188055) who was found to be compound heterozygous for factor V Leiden (612309.0001) and a null allele of the F5 gene resulting from a 4-bp insertion (2805insATTG) in exon 13. The insertion resulted in a frameshift and premature termination. The patient had 50% of normal levels of F5, all of which was of the Leiden type; hence he was 'pseudohomozygous' for factor V Leiden. Each of his 2 children inherited a different paternal factor V allele: the daughter was heterozygous for factor V Leiden, with 100% factor V activity, and the son was heterozygous for factor V deficiency, with 50% factor V activity and no factor V Leiden allele. The 4-bp insertion, designated factor V Stanford, was thus a factor V deficiency (227400) allele resulting in loss of protein function.
In a 19-year-old Korean woman with severe factor V deficiency (227400), van Wijk et al. (2001) identified compound heterozygosity for 2 mutations in the F5 gene: an 8-bp deletion in exon 7, at nucleotides 1131-1139, resulting in a frameshift and a premature stop codon (factor V Seoul-1), and a 5279A-G transition in exon 15 resulting in a tyr1702-to-cys (Y1702C; 612309.0007) substitution (factor V Seoul-2). The patient developed bleeding of the soft tissue of the mouth at the age of 19 months, experienced a large subdural hematoma at the age of 4 years, and suffered soft tissue bleeds of the mouth, epistaxis, and hematomas for which she received fresh frozen plasma once every 3 months. In recent years her bleeding pattern changed to spontaneous muscle bleedings. The patient was an orphan who had been adopted by a Dutch family at the age of 3 months and had no known relatives; thus it was not possible to determine directly that the Y1702C mutation was in trans to the 8-bp deletion. However, the same Y1702C mutation, associated with factor V deficiency, had been reported by Castoldi et al. (2000).
For discussion of the 5279A-G transition in exon 15 of the F5 gene, resulting in a tyr1702-to-cys (Y1702C) substitution (factor V Seoul-2), that was found in compound heterozygous state in a 19-year-old Korean woman with severe factor V deficiency (227400) by van Wijk et al. (2001), see 612309.0006.
In a 15-year-old girl from Morocco, the daughter of first-cousin parents, van Wijk et al. (2001) found that severe factor V deficiency with F5 activity less than 1% (227400) was caused by a homozygous 2491C-T transition in exon 13 of the F5 gene, resulting in a gln773-to-ter (Q773X) substitution. The patient was identified in the course of family screening. A 23-year-old brother, previously described by Tanis et al. (1998), also had severe factor V deficiency and prolonged bleeding after injuries. This mutation was designated factor V Casablanca.
In 2 seemingly unrelated southern Italian probands with undetectable plasma levels of factor V antigen and activity (227400), van Wijk et al. (2001) found homozygosity for the factor V Leiden mutation (612309.0001) in cis with a homozygous 3571C-T transition in exon 13 of the F5 gene, resulting in an arg1133-to-ter (R1133X) substitution and a truncated factor V molecule. Haplotype analysis suggested that an ancestral F5 Leiden allele, carrying the R1133X nonsense mutation in cis, diverged into the relatively rare haplotype identified in 1 of the probands by an intragenic crossing-over. Although the deficiency of the coagulation factor was profound, it was associated with only mild bleeding diathesis in 1 proband and the other proband was asymptomatic.
In a male infant with severe bleeding tendency and undetectable factor V activity (227400), Ajzner et al. (2002) found compound heterozygosity for 2 mutations in the F5 gene: a 1-bp deletion in exon 13 (2952delT) and a 1-bp insertion in exon 16 (5493insG; 612309.0011). Both mutations introduced a frameshift and a premature stop at codons 930 and 1776, respectively. The proband's father and mother were heterozygous for the 2 mutations, respectively. Both mutations resulted in the synthesis of truncated proteins lacking complete light chain or its C-terminal part.
For discussion of the 1-bp insertion (5493insG) in exon 16 of the F5 gene, resulting in a frameshift and a premature stop at codon 1776, that was found in compound heterozygous state in a male infant with severe bleeding tendency and undetectable factor V activity (227400) by Ajzner et al. (2002), see 612309.0010.
In a 22-year-old Italian woman in whom factor V deficiency (227400) was first diagnosed at the age of 10 years after abnormal coagulation screening tests were found preceding an operation for strabismus, Duga et al. (2003) identified a homozygous 6394C-T transition at in exon 23 of the F5 gene, resulting in an arg2074-to-cys (R2074C) change in the C2 domain of the protein. Functional studies showed that this substitution impaired both factor V secretion and its activity. The patient's menstruation was normal and her only bleeding symptom was easy bruising after minor trauma. Her parents, apparently nonconsanguineous, were asymptomatic and had factor V functional and antigen levels typical of heterozygotes.
In 2 Caucasian brothers with thrombophilia due to APC resistance (188055), Mumford et al. (2003) identified compound heterozygosity for 2 mutations in the F5 gene: a 1250T-C transition resulting in an ile359-to-thr (I359T) substitution, and a 529G-T transversion resulting in a glu119-to-ter mutation (E119X; 612309.0014). Both brothers developed spontaneous venous thromboses in the second decade of life. One presented at the age of 14 years with thrombosis of the right femoral vein and inferior vena cava; an older brother suffered recurrent episodes of femoral vein thrombosis from the age of 18 years and was managed with long-term warfarin therapy. Further investigation showed reduced coagulation factor V activity and APC resistance ratio but no other thrombophilic abnormalities. Heterozygous family members were asymptomatic. Mumford et al. (2003) speculated that the I359T substitution resulted in abnormal N-linked glycosylation of asn357 within the factor V A2 domain and that this resulted in reduced susceptibility of factor Va to proteolysis by APC. Mumford et al. (2003) suggested that the E119X mutation resulted in an mRNA that was recognized and degraded by the cell via a process termed nonsense-mediated decay. Thus, the authors concluded that hemizygosity for the I359T variant was the cause of severe early-onset thrombophilia in these sibs. The mutation was designated factor V Liverpool.
Steen et al. (2004) found that the I359T mutation appeared to affect anticoagulation by 2 mechanisms, impeding the APC-mediated downregulation of the factor Va molecule and additionally being a poor APC cofactor for the downregulation of factor VIIIa. They concluded that these findings explained the association of the I359T mutation with thrombosis.
For discussion of the 529G-T transversion in the F5 gene, resulting in a glu119-to-ter (E119X) substitution, that was found in compound heterozygous state in 2 Caucasian brothers with thrombophilia due to APC resistance (188055) by Mumford et al. (2003), see 612309.0013.
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