Molecular characterization of a multiethnic group of 21 patients with type3 von Willebrand disease

Type 3 von Willebrand disease is a rare autosomal disorder characterized by unmeasurable levels of von Willebrand factor and severe hemorrhagic sympto ms. We studied a multiethnic group of 37 patients, from Italy (n = 14), Ira n (n = 10) and India (n = 13) to identify the molecular defects and to eval uate genetic heterogeneity among these populations. Twenty-one patients (6 Italians, 9 Iranians and 6 Indians) were fully characterized at the molecul ar level. Twenty-Fuur different gene alterations were identified, 20 of whi ch have not been described previously. The majority of the mutations caused null alleles, 11 bring nonsense mutations (Q218*, W222*, R365*, R373*, E64 4*, Q706*, S1338*, Q1346*, Y1542*, R1659*, E2129*), 4 small deletions (437d elG, 2680delC, 6431delT, del 8491-8499), 3 possible splice sire mutations [ IVS9(-1)g->a, IVS29(+10)c->t, IVS40(-1)g->c], 3 candidate missense mutation s (C275S, C2174G, C2804Y), 2 small insertions (7375insC, 7921insC) and 1 la rge gene deletion. The latter mutation was associated with the development of alloantibodies to VWF, but this complication was also found in a patient homozygous for a nonsense mutation (Q1346*). Due to the ethnic origin of t he patients most of them were the offspring of consanguineous marriages and so were homozygous for the mutations found (18/21). Our results indicate t hat molecular defects responsible for type 3 VWD are scattered throughout t he entire VWF gene (from exon 3 to 52), and that there is no prevalent and common gene defect in the three populations studied by us.