EFFECTS OF THE MUTANT VON-WILLEBRAND-FACTOR GENE IN VON-WILLEBRAND DISEASE

Von Willebrand disease (vWD) is a common inherited bleeding disorder i n humans, and can be divided into a mild (type 1) and severe (type 3) form. Previous linkage studies identified one subject with vWD type 1 who transmitted different alleles of the von Willebrand factor (vWF) g ene to his two affected children, one having vWD type 3 and the other having type 1. By screening the promoter and coding sequence (52 exons ) of the vWF gene, three missense mutations were detected in this fami ly. The type 1 individual who transmitted different alleles of the gen e to his two sick children carries two substitutions, one in exon 5 an d the other in exon is on the respective alleles. The relationship bet ween the genotype (mutations) and the phenotype in this family is comp lex. In order further to correlate the relationship in vWD type 1 indi viduals, fifty-five subjects who carry one null allele of the VWF gene were collected. All these subjects are from vWD type 3 families with known mutations. Biochemical data of these 55 subjects indicate that g ene dosage and other factors, such as blood group, age, and environmen t factors, play a critical role in the development of the phenotype of the disease.