Mutations in the R2 FV Gene Affect the Ratio between the Two FV Isoforms in Plasma

Abstract

SummaryMolecular genetics and biochemical studies were performed in homozygotes for the R2 allele (4070G) in the factor V gene, most of them affected by coronary artery disease. Novel polymorphisms (G642T, 156Ser; T1328C, 385Met/Thr), among which a functional candidate (A6755G, 2194Asp/Gly) located in the C2 domain of FV, were identified in the R2 gene. In chromatographic studies R2 FV appeared qualitatively identical to normal FV. However, a relative increase of the more thrombogenic and more glycosylated FV isoform (FV1) was observed in plasma of 2194Gly homozygotes (mean FV1/FV2 ratio 0.71, 95% CI 0.66-0.77) as compared to R2-free controls (0.37, 95% CI 0.34-0.40). We conclude that carriership of the R2 FV gene is associated with an imbalance between the two functionally different FV isoforms, and propose that genetically determined differential glycosylation of FV could represent a novel mechanism of thrombotic disease.

Phenotype and genotype expression in pseudohomozygous R2 factor V

“…Thus, because of the absence of normal factor V in the patient's plasma, the factor V molecules resistant to APC inactivation are characterized by the mutations included in the HR2 haplotype. 7 These findings suggest the possibility that 1 or more of the amino acid substitutions predicted by the HR2 haplotype might impair factor Va cleavage at Arg506/ Arg306, possibly by preventing optimal interaction with APC. Alternatively, impaired factor Va inactivation may result from suboptimal interaction with phospholipid membranes.…”

Factor V: a combination of Dr Jekyll and Mr Hyde

“…143 This mutation (in the B region) is a marker that cosegregates with several other polymorphisms encoding several amino acid changes in the factor V molecule. [143][144][145][146] It has been reported that individuals carrying the factor V His1299Arg mutation have mild APC resistance and an increase in the risk of venous thrombosis. Thus, this ensemble of polymorphisms represents per se a potential thrombotic risk factor.…”

Aetiology of Venous Thrombosis

“…Later on, R2 polymorphism was found to be in tight association with at least 12 polymorphisms in the factor V gene. Therefore, these SNPs were collectively called HR2 (Haplotype R2) Castoldi et al, 2000). Several studies in different parts of the world gave the prevalence of HR2 to be 9.5%-15.2% in VTE cases and 5.8%-10.4% in healthy controls, with an increased risk by at least 2.5-fold Alhenc-Gelas et al, 1999;Castoldi et al, 2000;Pecheniuk et al, 2001;Margaglione et al, 2002;Castaman et al, 2003;Faioni et al, 2004;Jadaon & Dashti, 2005a).…”

“…The exact mechanism by which HR2 haplotype increases the risk for development of VTE is still not that clear. However, Castoldi et al (2000) have studied the two isoforms of factor V, V1 and V2, in cases with or without HR2. V1 is 7-fold more thrombogenic than V2.…”