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Blood, 15 February 2001, Vol. 97, No. 4, pp. 952-959
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
The arginine-552-cysteine (R1315C) mutation within the A1
loop of von Willebrand factor induces an abnormal folding with a loss
of function resulting in type 2A-like phenotype of von Willebrand
disease: study of 10 patients and mutated recombinant von
Willebrand factor
Anne-Sophie Ribba,
Lysiane Hilbert,
Jean-Maurice Lavergne,
Edith Fressinaud,
Catherine Boyer-Neumann,
Catherine Ternisien,
Irène Juhan-Vague,
Jenny Goudemand,
Jean-Pierre Girma,
Claudine Mazurier, and
Dominique Meyer
From the Institut National de la Santé et
de la Recherche Médicale (INSERM) U.143, Hôpital de
Bicêtre, Paris, France; the Laboratoire Français du
Fractionnement et des Biotechnologies and the Laboratoire
d'Hématologie CHU, Lille, France; the Laboratoire
d'Hématologie CHU, Nantes, France; the Laboratoire
d'Hémostase CHU, Angers, France; and the Laboratoire
d'Hématologie CHU, Marseilles, France.
The study identified 10 patients from 6 families with
prolonged bleeding time, decreased von Willebrand factor (vWF)
ristocetin cofactor activity (RCoF) to vWF:Ag (antigen)
ratio, and reduced ristocetin-induced platelet agglutination as well as
ristocetin- or botrocetin-induced binding of plasma vWF to platelet
glycoprotein Ib (GpIb). In addition, all patients showed a
decrease of intermediate-molecular-weight (intermediate-MW) and
high-molecular-weight (HMW) multimers of vWF. In the heterozygous
state, a cysteine-to-threonine (C  T) transversion was detected at
nucleotide 4193 of the VWF gene of all patients and
lead to the arginine (R)522C substitution in the A1 loop of vWF mature
subunit (R1315C in the preprovWF). By in vitro mutagenesis of
full-length complementary DNA (cDNA) of vWF and transient expression in
COS-7 cells, the mutated C552 recombinant vWF (C552rvWF) was found to
exhibit decreased expression, abnormal folding, and lack of
intermediate-MW and HMW multimers. In addition, direct binding of
botrocetin to C552rvWF, as well as ristocetin- and botrocetin-induced
binding of C552rvWF to GpIb, was markedly decreased. Although being
localized in an area of the A1 loop of vWF where most of the type 2B
mutations that induce a gain-of-function have been identified,
the R552C mutation induces a 2A-like phenotype with a decrease of
intermediate-MW and HMW multimers as well as a loss-of-function of vWF
in the presence of either ristocetin or botrocetin.
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