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Dominant type 1 von Willebrand disease caused by mutated cysteine residues
in the D3 domain of von Willebrand factor
JC Eikenboom, T Matsushita, PH Reitsma, EA Tuley, G Castaman, E Briet and JE Sadler
Department of Hematology, University Hospital, Leiden, The Netherlands.
No defects have been reported in moderately severe type 1 von Willebrand
disease (vWD) with a clear autosomal dominant inheritance pattern, and the
mechanism underlying this form of vWD remains obscure. We have studied a
type 1 vWD family with such a dominant phenotype. The entire coding
sequence of the von Willebrand factor (vWF) gene was analyzed by direct
sequencing of DNA fragments amplified by polymerase chain reaction. Only
one candidate mutation T(3445)-->C in exon 26 was detected that predicts
a replacement of cysteine (C) at position 386 of the mature vWF subunit by
arginine (R). Both mutant and normal vWF alleles were expressed as shown by
analysis of platelet mRNA. This substitution segregates with vWD in the
family and was not found in 100 unrelated individuals. The recombinant
mutant vWF(C386R) was characterized by expression in 293T cells. The
secretion of vWF(C386R) was greatly impaired due to retention in the
endoplasmic reticulum. In cotransfections of normal and mutant vWF
constructs, the vWF(C386R) subunits caused a dose-dependent decrease in the
secretion of vWF. The multimer pattern remained nearly normal and
consistent with a dominant vWD type 1 phenotype. The importance of the
cysteine residues in the D3 domain of vWF in the pathogenesis of dominant
type 1 vWD was further shown by the detection of another cysteine mutation,
Cys367-->Phe, in two additional unrelated patients with a similar
dominant type 1 vWD phenotype. We conclude that the loss of cysteine
pairing in the D3 domain, leaving one free cysteine, can induce a purely
quantitative deficiency of vWF by dominantly suppressing the secretion of
normal vWF.
Volume 88,
Issue 7,
pp. 2433-2441,
10/01/1996
Copyright © 1996 by The American Society of Hematology
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