The molecular defect in type IIB von Willebrand disease. Identification of four potential missense mutations within the putative GpIb binding domain.

Journal Article (Journal Article)

Type IIB von Willebrand Disease (vWD) is characterized by the selective loss of large von Willebrand Factor (vWF) multimers from plasma, presumably due to their increased reactivity with platelets and subsequent clearance from the circulation. Using the PCR, one of a panel of four potential missense mutations was identified in each of the 14 patients studied from 11 unrelated families. None of these substitutions was encountered in a large panel of normal DNAs. These changes all represent C----T transitions at CpG dinucleotides, proposed "hot spots" for mutation in the human genome. The four resulting amino acid substitutions, Arg543----Trp, Arg545----Cys, Val553----Met, and Arg578----Gln, are all clustered within the GpIb binding domain of vWF. Disruption of this latter functional domain may explain the pathogenesis of Type IIB vWD. By sequence polymorphism analysis, the Arg543----Trp substitution was shown to have occurred as at least two independent mutational events. This latter observation, along with the identification of mutations in all 14 patients studied and their localization to the GpIb binding domain, all strongly suggest that these substitutions represent the authentic defects responsible for Type IIB vWD. This panel of mutations may provide a useful diagnostic tool for the majority of patients with Type IIB vWD.

Full Text

Duke Authors

Cited Authors

  • Cooney, KA; Nichols, WC; Bruck, ME; Bahou, WF; Shapiro, AD; Bowie, EJ; Gralnick, HR; Ginsburg, D

Published Date

  • April 1991

Published In

Volume / Issue

  • 87 / 4

Start / End Page

  • 1227 - 1233

PubMed ID

  • 1672694

Pubmed Central ID

  • PMC295141

International Standard Serial Number (ISSN)

  • 0021-9738

Digital Object Identifier (DOI)

  • 10.1172/JCI115123


  • eng

Conference Location

  • United States