A NEW CANDIDATE MUTATION (N528S) WITHIN THE VON-WILLEBRAND-FACTOR PROPEPTIDE IDENTIFIED IN A JAPANESE PATIENT WITH PHENOTYPE IIC OF VON-WILLEBRAND-DISEASE

Phenotype IIC of von Willebrand disease (vWD) is a subtype of type 2A vWD characterized by recessive inheritance and an impaired multimeriza tion of von Willebrand factor (vWF) molecules beyond dimers. The 5 pat ients with phenotype IIC whose vWF gene defect has been characterized so far are either homozygous or double heterozygotes for mutations loc alized in exons 11, 12, 14 or 15. We report here the identification of a new candidate mutation in a previously described Japanese patient a ffected with phenotype IIC vWD. The propositus is homozygous for the A 1833G nucleotide substitution, in exon 14 of vWF gene, responsible for the N528S mutation within the vWF propeptide. This finding is in agre ement with the consanguineous origin of the propositus, whose parents are first cousins. Six patients' relatives who are asymptomatic were s tudied 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 p ropeptide region, where the other phenotype IIC mutations described so far are clustered. The N528S candidate mutation characterized is, the refore, most probably responsible for the multimerization defect of vW F observed in this patient.