Characterization of Leu777Pro and Ile865Thr type IIA von Willebrand disease
mutations
SE Lyons, KA Cooney, P Bockenstedt and D Ginsburg
Program in Cellular and Molecular Biology, Howard Hughes Medical Institute,
University of Michigan Medical School, Ann Arbor.
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.
Volume 83,
Issue 6,
pp. 1551-1557,
03/15/1994
Copyright © 1994 by The American Society of Hematology
