Expression studies on a novel type 2B variant of the von Willebrand factor gene (R1308L) characterized by defective collagen binding

L. Baronciani, A. B. Federici, M. Beretta, G. Cozzi, M. T. Canciani, P. M. Mannucci

Research output: Contribution to journalArticlepeer-review

Abstract

A novel mutation, R1308L (3923G > T) was present in the heterozygous state in five members of a family with type 2B von Willebrand disease (VWD) characterized by a full set of von Willebrand factor (VWF) multimers in plasma and by the absence of thrombocytopenia before and after desmopressin (DDAVP). The defect (R1308L) was located at the same amino acid position of one of the most common mutations associated with type 2B VWD (R1308C), which is characterized by the loss of high molecular weight VWF multimers (HMWM) in plasma and the occurrence of thrombocytopenia. To understand the mechanisms of this defect, the novel (R1308L) and 'common' (R1308C) mutations were expressed in COS-7 cells, either alone or, to mimic the patients' heterozygous state, together with wild-type VWF. R1308L recombinant VWF (rVWF) had a higher affinity for the platelet glycoprotein Ibα (GPIbα) receptor than wild-type rVWF, R1308C rVWF showing an even higher affinity. A novel finding was that both mutant rVWFs showed a similarly reduced binding to collagen type I and type III in comparison with wild-type rVWF. The latter finding suggests a more important role than recognized so far for the VWF A1 domain in VWF binding to collagen, which may contribute to the in vivo hemostatic defect associated with type 2B VWD.

Original languageEnglish
Pages (from-to)2689-2694
Number of pages6
JournalJournal of Thrombosis and Haemostasis
Volume3
Issue number12
DOIs
Publication statusPublished - Dec 2005

Keywords

  • Collagen
  • Expression study
  • Type 2B
  • Von Willebrand disease

ASJC Scopus subject areas

  • Medicine(all)

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