New mutations in exon 28 of the von Willebrand factor gene detected in patients with different types of von Willebrand's disease

Background and Objectives. von Willebrand's disease (vWD), the most common hereditary bleeding disorder in humans, is caused by qualitative and/or qua ntitative deficiencies of von Willebrand factor, and can manifest itself un der several different phenotypes. Most of the molecular defects have been d etected in qualitative variants involving exon 28 of the vWF gene. Patients from four unrelated families with different types of vWD were included in the mutation screening of this region. Design and Methods. The whole exon 28 was analyzed in three gene specific f ragments, two of them comprising the region involved in the platelet glycop rotein Ib vWF interaction. The search for mutations was carried out by sing le-stranded conformation polymorphism analysis. The mutations were then ide ntified by automatic sequencing of the anomalous electrophoretic pattern sa mples. Results. The following candidate mutations were detected. The 3941T-->A tra nsversion, which predicts the amino acid change V1314D, was detected in a s poradic patient with type 28 vWD and severe thrombocytopenia, The 4309G-->A transition, resulting in the amino acid substitution A1437T, was identifie d in four patients classified as having type 2M vWD. Six unclassified patie nts from another family carry the 4135C-->T mutation, which gives rise to a cysteine instead of the normal arginine (R1379C) that segregates with the phenotype. The amino acid change C1227R, predicted by the mutation 4135C--> T, was identified as a compound heterozygote in a patient with moderately s evere type 1 vWD, None of these mutations had been described previously. Interpretation and Conclusions. These findings confirm the importance alrea dy given to this region for the correct function of von Willebrand factor s ince the mutations detected, which affect the D3 and Al domains, could give rise to different variants of the disease. (C) 2001, Ferrata Storti Founda tion.