A COMMON FRAMESHIFT MUTATION IN VON-WILLEBRAND-FACTOR DOES NOT ALTER MESSENGER-RNA STABILITY BUT INTERFERES WITH NORMAL PROPEPTIDE PROCESSING

Quantitative defects in von Willebrand factor (VWF) result in type 1 a nd type 3 von Willebrand disease (VMD). This study characterizes the d efect in VWF expression resulting from a single nucleotide deletion in VWF exon is, a mutation previously reported to be common among type 3 VWD patients. A severely affected (type 3) VWD patient in the current pedigree is homozygous for the mutation, whereas heterozygous individ uals exhibit variable expression of type 1 VWD. In contrast to the pre viously reported high frequency of the exon 18 deletion in Sweden and Germany, this mutation appears to be infrequent among type 3 VWD patie nts in the United States. Although this frameshift mutation results in proximal premature termination of VWF translation, the abnormal VWF m RNA is stable. The mutant truncated recombinant VWF protein is retaine d within the transfected cell, and no propeptide processing is observe d, suggesting a defect in protein folding. Cotransfection of mutant an d wild-type recombinant VWF fails to demonstrate a dominant effect of the mutant on the normal allele. Consistent with these results, plasma VWF propeptide of the homozygous individual was markedly reduced wher eas heterozygotes exhibited moderately reduced levels. In contrast to type 2A VWD (group 1), the misfolded mutant protein does not appear to exert a dominant-negative effect on normal VWF subunits expressed fro m the wild-type allele.