title: von Willebrand factor variant p.Arg924Gln marks an allele associated with reduced von Willebrand factor and factor VIII levels.
abstract: 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.
  
  
  OBJECTIVE
  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-1VWD 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.
authors.affiliation: Haemostasis Research Group, Department of Cardiovascular Science, University of Sheffield, Sheffield, UK.
authors.forename: N
authors.initials: N
authors.lastname: Hickson
authors.forename: D
authors.initials: D
authors.lastname: Hampshire
authors.forename: P
authors.initials: P
authors.lastname: Winship
authors.forename: J
authors.initials: J
authors.lastname: Goudemand
authors.forename: R
authors.initials: R
authors.lastname: Schneppenheim
authors.forename: U
authors.initials: U
authors.lastname: Budde
authors.forename: G
authors.initials: G
authors.lastname: Castaman
authors.forename: F
authors.initials: F
authors.lastname: Rodeghiero
authors.forename: A B
authors.initials: AB
authors.lastname: Federici
authors.forename: P
authors.initials: P
authors.lastname: James
authors.forename: I
authors.initials: I
authors.lastname: Peake
authors.forename: J
authors.initials: J
authors.lastname: Eikenboom
authors.forename: A
authors.initials: A
authors.lastname: Goodeve
mesh_terms: D000017:ABO Blood-Group System; D000483:Alleles; D001120:Arginine / Q000235:genetics*; D016022:Case-Control Studies; D005169:Factor VIII / Q000235:genetics*; D018703:Founder Effect; D014644:Genetic Variation; D005838:Genotype; D005973:Glutamine / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D010641:Phenotype; D011994:Recombinant Proteins / Q000737:chemistry; D014842:von Willebrand Diseases / Q000235:genetics*; D014841:von Willebrand Factor / Q000737:chemistry / Q000235:genetics*
chemical_list: D000017:ABO Blood-Group System; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D005973:Glutamine; D005169:Factor VIII; D001120:Arginine