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Functional analysis of a type IIB von Willebrand disease missense mutation: increased binding of large von Willebrand factor multimers to platelets.

Publication ,  Journal Article
Cooney, KA; Lyons, SE; Ginsburg, D
Published in: Proc Natl Acad Sci U S A
April 1, 1992

Type IIB von Willebrand disease is an autosomal dominant bleeding disorder characterized by the selective loss of high molecular weight von Willebrand factor (vWF) multimers in plasma, presumably due to their abnormally increased reactivity with platelets. We and others have recently identified a panel of missense mutations clustered in the platelet glycoprotein Ib binding domain of vWF from patients with type IIB von Willebrand disease. We now report functional analysis of one of the most frequent type IIB missense mutations, Arg-543----Trp (vWF R543W). vWF from a human umbilical vein endothelial cell culture heterozygous for the vWF R543W mutation showed markedly increased binding of large vWF multimers to platelets in the presence of a low dose of ristocetin compared to vWF from a normal control culture. Recombinant vWF containing the vWF R543W mutation expressed in COS-7 cells also demonstrated increased binding of large vWF multimers. Mixed multimers obtained by cotransfection of mutant and wild-type cDNAs showed partial dominance of the vWF R543W mutation. Thus these data demonstrate that the vWF R543W mutation alone is sufficient to confer increased binding of large vWF multimers to platelets in a dominant fashion and that no other factors relating to vWF posttranslational processing or secretion in endothelial cells are required for this effect.

Duke Scholars

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

April 1, 1992

Volume

89

Issue

7

Start / End Page

2869 / 2872

Location

United States

Related Subject Headings

  • von Willebrand Factor
  • von Willebrand Diseases
  • Ristocetin
  • Recombinant Proteins
  • Platelet Membrane Glycoproteins
  • Platelet Aggregation
  • Mutation
  • Macromolecular Substances
  • Humans
  • Endothelium, Vascular
 

Citation

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Cooney, K. A., Lyons, S. E., & Ginsburg, D. (1992). Functional analysis of a type IIB von Willebrand disease missense mutation: increased binding of large von Willebrand factor multimers to platelets. Proc Natl Acad Sci U S A, 89(7), 2869–2872. https://doi.org/10.1073/pnas.89.7.2869
Cooney, K. A., S. E. Lyons, and D. Ginsburg. “Functional analysis of a type IIB von Willebrand disease missense mutation: increased binding of large von Willebrand factor multimers to platelets.Proc Natl Acad Sci U S A 89, no. 7 (April 1, 1992): 2869–72. https://doi.org/10.1073/pnas.89.7.2869.
Cooney, K. A., et al. “Functional analysis of a type IIB von Willebrand disease missense mutation: increased binding of large von Willebrand factor multimers to platelets.Proc Natl Acad Sci U S A, vol. 89, no. 7, Apr. 1992, pp. 2869–72. Pubmed, doi:10.1073/pnas.89.7.2869.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

April 1, 1992

Volume

89

Issue

7

Start / End Page

2869 / 2872

Location

United States

Related Subject Headings

  • von Willebrand Factor
  • von Willebrand Diseases
  • Ristocetin
  • Recombinant Proteins
  • Platelet Membrane Glycoproteins
  • Platelet Aggregation
  • Mutation
  • Macromolecular Substances
  • Humans
  • Endothelium, Vascular