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Hickson, N.; Hampshire, D.; Winship, P.; Goudemand, J.; Schneppenheim, R.; Budde, U.; ... ; ZPMCB -VWD Study Grp (2010)

von Willebrand factor variant p.Arg924Gln marks an allele associated with reduced von Willebrand factor and factor VIII levels

Article / Letter to editor
Background: von Willebrand factor (VWF) variant c.2771G > A; p.R924Q has been described as a benign polymorphism or a possible marker for a null allele and been associated with mild bleeding phenotypes. It was identified in several patients in recent type 1 von Willebrand disease (VWD) studies. Objectives: To determine whether the p.R924Q allele contributes to reduced VWF levels and type 1 VWD. Methods: One thousand one hundred and fifteen healthy controls and 148 index cases from the MCMDM-1 VWD study were genotyped for c.2771G > A; VWF and FVIII levels were analyzed in ABO blood group stratified individuals and the p.R924Q variant was expressed in 293 EBNA cells. Results: c.2771G > A was present in six index cases, five of whom had a second VWF variant which probably contributed to the phenotype. A common core haplotype identified in families, which included the rare G allele of c.5843-8C > G, was present in the majority of 35 c.2771G > A heterozygous controls. c.2771G > A...Show moreBackground: von Willebrand factor (VWF) variant c.2771G > A; p.R924Q has been described as a benign polymorphism or a possible marker for a null allele and been associated with mild bleeding phenotypes. It was identified in several patients in recent type 1 von Willebrand disease (VWD) studies. Objectives: To determine whether the p.R924Q allele contributes to reduced VWF levels and type 1 VWD. Methods: One thousand one hundred and fifteen healthy controls and 148 index cases from the MCMDM-1 VWD study were genotyped for c.2771G > A; VWF and FVIII levels were analyzed in ABO blood group stratified individuals and the p.R924Q variant was expressed in 293 EBNA cells. Results: c.2771G > A was present in six index cases, five of whom had a second VWF variant which probably contributed to the phenotype. A common core haplotype identified in families, which included the rare G allele of c.5843-8C > G, was present in the majority of 35 c.2771G > A heterozygous controls. c.2771G > A contributed about 10% variance in VWF and FVIII levels in controls and 35% variance when co-inherited with blood group O. Recombinant p.R924Q VWF had no effect on in vitro expression and heterozygous family members had normal VWF-FVIII binding and normal clearance of VWF and FVIII. Conclusions: The allele bearing c.2771A leads to reductions in VWF and FVIII levels particularly in combination with blood group O. Its inheritance alone may be insufficient for VWD diagnosis, but it appears to be associated with a further VWF level reduction in individuals with a second VWF mutation and it contributes to population variance in VWF and FVIII levels.Show less
ABO blood group factor VIII founder effect R924Q type 1 von Willebrand disease von Willebrand factor clinical markers disease mcmdm-1vwd linkage analysis phenotype vwd management diagnosis genotype r924q substitution
All authors
Hickson, N.; Hampshire, D.; Winship, P.; Goudemand, J.; Schneppenheim, R.; Budde, U.; Castaman, G.; Rodeghiero, F.; Federici, A.B.; James, P.; Peake, I.; Eikenboom, J.; Goodeve, A.; MCMDM-VWD Grp; ZPMCB -VWD Study Grp
Date
2010-09-30
Journal
Journal of Thrombosis and Haemostasis
Volume
8
Issue
9
Pages
1986 - 1993
DOI
doi:10.1111/j.1538-7836.2010.03927.x