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Prepublished online as a Blood First Edition Paper on August 8, 2002; DOI 10.1182/blood-2002-04-1046.
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Blood, 1 January 2003, Vol. 101, No. 1, pp. 151-156
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
An Arg760Cys mutation in the consensus sequence of the von
Willebrand factor propeptide cleavage site is responsible for a new von
Willebrand disease variant
Alessandra Casonato,
Francesca Sartorello,
Maria
Grazia Cattini,
Elena Pontara,
Carmen Soldera,
Antonella Bertomoro, and
Antonio Girolami
From the Department of Medical and Surgical Sciences,
Second Chair of Internal Medicine, University of Padua, Medical School,
Padua, Italy.
We describe a von Willebrand disease (VWD) variant characterized by
the persistence of von Willebrand factor (VWF) propeptide as a result
of a C>T transition at nucleotide 2527 in exon 17 of the VWF gene.
This mutation, which was present in the proband and his father,
predicts the substitution of Cys for Arg at position 760 of
pre-pro-VWF, 4 residues before the propeptide cleavage site belonging
to a consensus sequence for substrate recognition by the processing
enzyme paired dibasic amino acid-cleaving enzyme (PACE)/furin.
Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) documented the presence of both processed and unprocessed VWF in the patient's plasma, with unprocessed VWF relatively
less represented. The patient's hemostatic phenotype was characterized by a mild decrease in plasma factor VIII (FVIII) and VWF, a
decrease in plasma VWF multimers, and a mild reduction in the FVIII
binding capacity of VWF. The FVIII binding defect was more pronounced in the proband than in the father because he also inherited the type 2N
Arg91Gln mutation from his mother. The persistence of VWF propeptide
did not impair VWF synthesis because platelet VWF content was normal,
nor did it compromise VWF storage in endothelial cells, because of the
normal post-1-deamino-8-D-arginine vasopressin (DDAVP)
increase in plasma VWF. Coexpression of wild-type and Arg760Cys VWF
into a Furin-producing BHK cell line resulted in decreased VWF
secretion and a defect in the FVIII binding capacity of VWF, together
with the persistence of VWF propeptide. These findings confirm that a
normal consensus sequence for VWF propeptide cleavage and efficient
cleavage are required in vivo for normal FVIII binding capacity of VWF.
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