IN-FRAME DELETION OF VONWILLEBRAND FACTOR-A DOMAINS IN A DOMINANT TYPE OF VONWILLEBRAND DISEASE

von Willebrand disease (vWD), the most common inherited bleeding disor der in humans, is very heterogeneous and has been classified into seve ral subtypes. Missense mutations have been found to be responsible for the dominant type II vWD, characterized by qualitative abnormalities affecting von Willebrand factor (vWF) function. The breakpoints of a h eterozygous vWF gene deletion (31 Kb), occurring 'de novo' in a patien t with a variant of type II vWD, were localized to introns 25 and 34 a nd sequenced. An Alu repeat in intron 25 was interrupted between the t ranscriptional boxes A and B.The new junction present in the abnormal von Willebrand factor mRNA was sequenced after reverse transcription o f platelet RNA. The codon 1104 (Cys) is followed in frame by the mutat ed codon 1926 (Cys to Arg), thus removing the complete A domains, foun d in a wide variety of genes and characterized by independent assembly 'in vitro'. We propose that the abnormal vWF, which carries intact pr otein domains responsible for vWF dimer and multimer formation, makes ineffective interactions with the normal molecules in the biosynthetic process, causing the dominant type II phenotype through a novel mecha nism.