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

SummaryThe 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.

The Y/C1584 mutation of von Willebrand factor in type 2M von Willebrand disease: frequency and clearance of von Willebrand factor

“…The normal VWF:Ag t 1/2 observed in the two patients with type 2M VWD contrasts with the shortened VWF:Ag t 1/2 demonstrated in patients with type 1 VWD, irrespective of the presence of the Y/C1584 mutation (Millar et al, 2004). In summary, the frequency of the Y/C1584 mutation observed in these 14 families with type 2M VWD is comparable with the reported frequencies in families with type 1 VWD (26AE6%, Bowen et al, 2005 and;14AE3%, O'Brien et al, 2003). The frequency of Y/C1584 mutation in the normal population was reported to be 0% and 1% in these two studies (O'Brien et al, 2003;Bowen & Collins, 2004).…”

“…Bowen et al (2005) reported an increased prevalence of this mutation in families with type 1 VWD, but the presence of C1584 did not correlate with disease status (Bowen et al, 2005). The presence of C1584 was shown to result in increased susceptibility of von Willebrand factor (VWF) to proteolysis by the metalloprotease ADAMTS-13 in both affected and unaffected individuals.…”

Investigation of von Willebrand Factor Gene Mutations in Korean von Willebrand Disease Patients

“…Recently, it was reported that Y1584C substitution renders VWF susceptible to the action of ADAMTS13 and consequently results in increased clearance of VWF from plasma [19]. Actually the corresponding allele was found to be overly represented in type 1 VWD patients and their families by 25% and 27% respectively, compared with about 1% in general population [20]. The frequency of C1584 allele in east Asians is nearly zero (Entrez SNP database) and accordingly the substitution Y1584C was not found among VWD patients included in our study.…”

“…First, we reexamined the sequencing data for the presence of polymorphism Y1584C, which was recently reported to be prevalent in type 1 VWD implicating the susceptibility to AD-AMTS13 as an important factor influencing the development of VWD [19,20]. But there was not a case with C1584 allele among the forty patients.…”

“…Methods : In 40 known vWD patients mutations of vWF gene were sought by direct sequencing of PCR products targeting exons 18,19,20,26,28 and 52 frequently implicated as the locations of mutation. For factors other than VWF gene contributing to VWD phenotype, we tested ABO blood group and measured ADAMTS13 activity in VWD patients.…”