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Identification of two mutations (Arg611Cys and Arg611His) in the A1 loop of
von Willebrand factor (vWF) responsible for type 2 von Willebrand disease
with decreased platelet-dependent function of vWF [see comments]
L Hilbert, C Gaucher and C Mazurier
Laboratoire de Recherche sur l'Hemostase, Centre Regional de Transfusion
Sanguine de Lille, France.
We report the identification of von Willebrand factor (vWF) gene mutations
within exon 28 occurring in three unrelated families with an infrequent
form of type 2 von Willebrand disease (vWD). A C-->T transition and a
G-->A transition, both at the codon for arginine 611 of the mature vWF
subunit, were found. They result in either a cysteine or an histidine
substitution, respectively. Patients were found to be heterozygous for
these substitutions and the vWD was transmitted dominantly. These
substitutions have been reproduced by in vitro mutagenesis of full-length
cDNA of vWF and transiently expressed in Cos- 7 cells. The corresponding
recombinant vWFs (rvWF) exhibited decreased expression and a significant
decrease in the high molecular weight multimeric forms. In addition,
ristocetin- and botrocetin-induced binding of mutated rvWFs to platelets
were markedly decreased as compared with that for the wild-type rvWFs.
Thus, the structural and functional characterization of both mutated rvWFs
confirmed that the two nucleotide substitutions identified at position 611
of the mature subunit of vWF are real mutations. Although they are located
in the A1 loop containing most of the type 2B mutations inducing increased
affinity of vWF for platelet glycoprotein Ib, they are responsible for
abnormal vWF with decreased platelet-dependent function.
Volume 86,
Issue 3,
pp. 1010-1018,
08/01/1995
Copyright © 1995 by The American Society of Hematology
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