The von Willebrand factor gene and genetics of von Willebrand's disease.

The von Willebrand factor (vWF) gene spans 178 kilobases in the human genome, is interrupted by 51 introns, and has been localized to human chromosome 12p12----12pter. In addition, a pseudogene that duplicates the midportion of the vWF gene has been identified on chromosome 22. In several families, large vWF gene deletions have been identified as the basis for von Willebrand's disease (vWD). In most patients, however, the vWF gene is found to be grossly intact by Southern blot analysis, a result that implies a more subtle molecular defect. The advent of the polymerase chain reaction has allowed a more direct analysis in this group of patients. By this approach, missense mutations, all clustered within the same small region in the midportion of the vWF molecule, have been identified in several patients with type IIA vWD. Expression of mutant vWF by transfection into COS cells suggests that the characteristic loss of high-molecular-weight multimers seen in type IIA vWD may occur through at least two distinct mechanisms. In preliminary studies of nondeletional type III vWD, a family has been identified with decreased vWF as a result of failure of production of messenger RNA from the affected vWF allele. This disorder could be due to defects in vWF gene transcription, RNA processing, or stability. As additional defects are identified, the accurate diagnosis of vWD at the molecular level may eventually become possible.