title: The prevalence of the cysteine1584 variant of von Willebrand factor is increased in type 1 von Willebrand disease: co-segregation with increased susceptibility to ADAMTS13 proteolysis but not clinical phenotype.
abstract: The molecular pathogenesis of type 1 von Willebrand disease (VWD) is uncertain in most patients. We examined 30 type 1 VWD families in the UK Haemophilia Centre Doctors' Organization study. Heterozygosity for Y/C1584 was present in eight of 30 (27%) families and 19 of 76 (25%) individuals with type 1 VWD recruited into the study. Eighteen (95%) of these 19 individuals were blood group O. C1584 did not co-segregate with VWD in four families, and co-segregated in one family; the results were equivocal in three families. In all families increased susceptibility of von Willebrand factor (VWF) to a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) 13 proteolysis co-segregated with C1584 in affected and unaffected individuals. These data show that C1584, associated with blood group O, is prevalent among patients with type 1 VWD but not necessarily causative of disease and should not be used in isolation to diagnose VWD. Increased susceptibility of C1584 VWF to ADAMTS13 proteolysis may be physiologically significant and increase an individual's risk of bleeding and presenting with VWD.
authors.affiliation: Department of Haematology, University of Wales College of Medicine, Cardiff GF14 4XN, UK.
authors.forename: Derrick J
authors.initials: DJ
authors.lastname: Bowen
authors.forename: Peter W
authors.initials: PW
authors.lastname: Collins
authors.forename: Will
authors.initials: W
authors.lastname: Lester
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Cumming
authors.forename: Steven
authors.initials: S
authors.lastname: Keeney
authors.forename: Pamela
authors.initials: P
authors.lastname: Grundy
authors.forename: Saad M
authors.initials: SM
authors.lastname: Enayat
authors.forename: Paula H B
authors.initials: PH
authors.lastname: Bolton-Maggs
authors.forename: David M
authors.initials: DM
authors.lastname: Keeling
authors.forename: Kate
authors.initials: K
authors.lastname: Khair
authors.forename: R Campbell
authors.initials: RC
authors.lastname: Tait
authors.forename: Jonathon T
authors.initials: JT
authors.lastname: Wilde
authors.forename: K John
authors.initials: KJ
authors.lastname: Pasi
authors.forename: Frank G H
authors.initials: FG
authors.lastname: Hill
mesh_terms: D000017:ABO Blood-Group System; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; D015331:Cohort Studies; D003545:Cysteine / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D014842:von Willebrand Diseases / Q000097:blood / Q000235:genetics*
chemical_list: D000017:ABO Blood-Group System; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human; D003545:Cysteine