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Prepublished online as a Blood First Edition Paper on August 8, 2002; DOI 10.1182/blood-2002-04-1046.
Submitted April 4, 2002
Accepted July 10, 2002
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 A Casonato*, Francesca Sartorello, Maria Grazia Cattini, Elena Pontara, Carmen Soldera, Antonella Bertomoro, and Antonio Girolami
Department of Medical and Surgical Sciences, University of Padua Medical School, Padua, Italy
* Corresponding author; email: sandra.casonato{at}unipd.it.
We describe a von Willebrand disease (VWD) variant characterized by the persistence of von Willebrand factor (VWF ) propeptide due to a C-to-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 cysteine for arginine 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 PACE/furin. SDS-PAGE documented the presence of both processed and unprocessed VWF in the patients plasma, with unprocessed VWF relatively less represented. The patients haemostatic phenotype was characterized by a mild decrease in plasma 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, due to the normal post-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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