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Blood, 1 April 2001, Vol. 97, No. 7, pp. 2059-2066
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Expression and characterization of von Willebrand factor
dimerization defects in different types of von Willebrand
disease
Reinhard Schneppenheim,
Ulrich Budde,
Tobias Obser,
Jacqueline Brassard,
Kerstin Mainusch,
Zaverio M. Ruggeri,
Sonja Schneppenheim,
Rainer Schwaab, and
Johannes Oldenburg
From Pediatric Hematology and Oncology, University
Children's Hospital, Hamburg, Germany; Lab Association Keeser, Arndt
and Partners, Coagulation Lab, Hamburg, Germany; Searle/Monsanto,
Investigative and Discovery Pathology, St Louis, MO; the Scripps
Research Institute, La Jolla, CA; and the Institute of Experimental
Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany.
Dimerization defects of von Willebrand factor (vWF) protomers
underlie von Willebrand disease (vWD) type 2A, subtype IID (vWD 2A/IID), and corresponding mutations have been identified at the 3' end
of the vWF gene in exon 52. This study identified and expressed 2 additional mutations in this region, a homozygous defect in a patient
with vWD type 3 (C2754W) and a heterozygous frameshift mutation
(8566delC) in a patient with vWD type 2A, subtype IIE. Both mutations
involve cysteine residues that we propose are possibly essential for
dimerization. To prove this hypothesis, transient recombinant
expression of each of the 2 mutations introduced in the
carboxy-terminal vWF fragment II and in the complete vWF
complementary DNA, respectively, were carried out in COS-7 cells
and compared with expression of vWD 2A/IID mutation C2773R and the
wild-type (WT) sequence in COS-7 cells. Recombinant WT vWF fragment II
assembled correctly into a dimer, whereas recombinant mutant fragments
were monomeric. Homozygous expression of recombinant mutant full-length vWF resulted in additional dimers, probably through disulfide bonding
at the amino-terminal multimerization site, whereas recombinant WT vWF correctly assembled into multimers. Coexpression of
recombinant mutant and recombinant WT vWF reproduced the multimer
patterns observed in heterozygous individuals. Our results suggest that a common defect of vWF biosynthesis lack of vWF dimerizationmay cause diverse types and subtypes of vWD. We also confirmed
previous studies that found that disulfide bonding at the vWF
amino-terminal is independent of dimerization at the vWF
carboxy-terminal.
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