Characterization of Leu777Pro and Ile865Thr type IIA von Willebrand disease mutations.


Journal Article

Type IIA von Willebrand disease (vWD) is an autosomal dominant bleeding disorder characterized by a qualitative defect in von Willebrand factor (vWF). A number of missense mutations responsible for type IIA vWD have recently been identified. This report examines the type IIA vWD mutations Leu777-->Pro and Ile865-->Thr by expression of recombinant vWF containing mutant and wild-type (WT) sequences. Recombinant vWF containing the L777P mutation (vWFL777P) showed markedly impaired secretion compared with that for wild-type vWF (vWFWT) after DNA transfection into mammalian cells. Multimer analysis of secreted vWFL777P showed predominantly low molecular weight forms. In contrast, recombinant vWF containing the I865T mutation (vWFI865T) was processed in a pattern similar to vWFWT, with secretion of the full spectrum of vWF multimers. Thus, L777P and I865T are subclassified as type IIA group I and group II mutations, respectively. Analysis of platelet vWF from a patient heterozygous for the L777P mutation shows reduced large vWF multimers in a pattern similar to plasma, consistent with the intracellular transport defect predicted for a group I mutation. An increase in the proportion of high molecular weight multimers observed in type IIA vWD patient plasma, after renal transplantation from a normal donor, suggests that the kidney endothelium may be a major source of plasma vWF.

Full Text

Duke Authors

Cited Authors

  • Lyons, SE; Cooney, KA; Bockenstedt, P; Ginsburg, D

Published Date

  • March 1994

Published In

Volume / Issue

  • 83 / 6

Start / End Page

  • 1551 - 1557

PubMed ID

  • 8123844

Pubmed Central ID

  • 8123844

Electronic International Standard Serial Number (EISSN)

  • 1528-0020

International Standard Serial Number (ISSN)

  • 0006-4971


  • eng