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Expressed full-length von Willebrand factor containing missense mutations
linked to type IIB von Willebrand disease shows enhanced binding to
platelets
PA Kroner, ML Kluessendorf, JP Scott and RR Montgomery
Blood Research Institute, Blood Center of Southeastern Wisconsin, Milwaukee
53233.
von Willebrand disease (vWD) variant type IIB is an inherited bleeding
disorder resulting from the spontaneous binding of defective von Willebrand
factor (vWF) to platelets in vivo. To identify the molecular basis for type
IIB vWD, we used reverse transcription and the polymerase chain reaction to
examine the nucleotide sequence of the platelet glycoprotein (GP)
Ib-binding domain encoded by the vWF messenger RNA in an affected family,
and in an unrelated affected individual. We identified two different
missense mutations linked with expression of type IIB vWD. These mutations,
which lead to Pro574---- Leu and Val553----Met substitutions, respectively,
were each introduced into the full-length vWF expression vector pvW198, and
both wild-type (wt) and mutant vWF were transiently expressed in COS-7
cells. Binding assays showed that both mutant proteins showed significant
non- ristocetin-dependent spontaneous binding to platelets, and that
complete binding was induced by low concentrations of ristocetin that
failed to induce platelet binding by wt vWF. The vWF/platelet interaction
was inhibited by the anti-vWF monoclonal antibody (MoAb) AvW3, and the
anti-GPIb MoAb AP1, which both block vWF binding to platelets. These
results show that the identified missense mutations are the likely basis
for the expression of type IIB vWD in these affected individuals.
Volume 79,
Issue 8,
pp. 2048-2055,
04/15/1992
Copyright © 1992 by The American Society of Hematology
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