Analysis of Arg834Gln and Val902Glu type 2A von Willebrand disease
mutations: studies with recombinant von Willebrand factor and correlation
with patient characteristics
T Englender, A Lattuada, PM Mannucci, JE Sadler and A Inbal
Department of Hematology, Sheba Medical Center, Tel Hashomer, Israel.
Type 2A von Willebrand disease (vWD), the most common qualitative form of
vWD, is characterized by a relative decrease in circulating intermediate
and high molecular weight (HMW) multimers. We studied the biosynthesis of
recombinant von Willebrand factor (vWF) containing each of two type 2A vWD
mutations previously reported by us, Arg834Gln and Val902Glu. The structure
of recombinant Arg834Gln vWF within transfected COS-7 cells and the
secretion of HMW multimers were similar to wild type vWF. The normal
transport and secretion of Arg834Gln vWF, categorizes it as a group II type
2A mutation. In contrast, the Val90- 2Glu mutation resulted in
intracellular proteolysis of vWF with the generation of a 176-kD fragment
and retention of vWF between the endoplasmic reticulum and the Golgi
complex. Moreover, the 176-kD fragment was also increased in plasma from
patients with the Val902Glu mutation. Significantly impaired secretion and
intracellular proteolysis of Val902Glu vWF categorizes a new sub-group of
type 2A mutations. The intracellular proteolysis of vWF Val902Glu explains
the lack of response to 1-deamino 8-D-arginine vasopressin (DDAVP) in
patients who carry the mutation.
Volume 87,
Issue 7,
pp. 2788-2794,
04/01/1996
Copyright © 1996 by The American Society of Hematology
