A new candidate mutation (N528S) within the von Willebrand factor propeptide identified in a Japanese patient with phenotype IIC of von Willebrand disease

Abstract

Phenotype IIC of von Willebrand disease (vWD) is a subtype of type 2A vWD characterized by recessive inheritance and an impaired multimerization of von Willebrand factor (vWF) molecules beyond dimers. The 5 patients with phenotype IIC whose vWF gene defect has been characterized so far are either homozygous or double heterozygotes for mutations localized in exons 11, 12, 14 or 15. We report here the identification of a new candidate mutation in a previously described Japanese patient affected with phenotype IIC vWD. The propositus is homozygous for the A1833G nucleotide substitution, in exon 14 of vWF gene, responsible for the N528S mutation within the vWF propeptide. This finding is in agreement with the consanguineous origin of the propositus, whose parents are first cousins. Six patients' relatives who are asymptomatic were studied and found heterozygous for the N528S mutation. The screening of the whole vWF gene, either by SSCP or sequencing, did not reveal any other deleterious sequence alteration in the patient. Furthermore, the N528S nonconservative substitution identified is located in the vWF propeptide region, where the other phenotype IIC mutations described so far are clustered. The N528S candidate mutation characterized is, therefore, most probably responsible for the multimerization defect of vWF observed in this patient.