A G sub(+3)-to-T donor splice site mutation leads to skipping of exon 50 in Von Willebrand factor mRNA

Von Willebrand disease (vWD) is the most frequent human bleeding disorder. It results from quantitative (types I and III) and qualitative (type II) defects of von Willebrand factor (vWF), a large multimeric glycoprotein that plays several critical roles in hemostasis. More than 20 distinct clinical and laboratory subtypes have been characterized, and a variety of mutations, mainly associated with type II, have been identified. For the most severe form of vWD (type III), which is characterized by extremely low to undetectable levels of vWF and autosomal recessive inheritance, only a few defects in the vWF gene have been observed. As yet, no mutation that affects the region corresponding to amino acid residues 1927 to 2050 of the carboxy-terminus of vWF protein has been described. Dimerization of vWF, which represents the initial step of vWF multimer formation, is directed by 1 or more of the 16 cysteine residues in this area. Thus, we have analyzed the corresponding part of the 178-kb vWF gene and its 9-kb mRNA transcript.