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Blood, 15 October 2009, Vol. 114, No. 16, pp. 3489-3496. Prepublished online as a Blood First Edition Paper on August 17, 2009; DOI 10.1182/blood-2008-10-184317. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-10-184317v1 114/16/3489    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Riddell, A. F. Articles by McKinnon, T. A. J. PubMed PubMed Citation Articles by Riddell, A. F. Articles by McKinnon, T. A. J. Related Collections Thrombosis and Hemostasis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  THROMBOSIS AND HEMOSTASIS Characterization of W1745C and S1783A: 2 novel mutations causing defective collagen binding in the A3 domain of von Willebrand factor Anne F. Riddell1, Keith Gomez1, Carolyn M. Millar1, Gillian Mellars1, Saher Gill2, Simon A. Brown1,3, Megan Sutherland4, Mike A. Laffan2, and Thomas A. J. McKinnon2 1 Katharine Dormandy Haemophilia Centre and Thrombosis Unit, The Royal Free and University College Medical School, London, United Kingdom; 2 Department of Haematology, Imperial College Academic Health Sciences Centre, Hammersmith Hospital, London, United Kingdom; 3 Department of Haematology, Royal Children's Hospital and Royal Brisbane and Women's Hospital, Brisbane, Australia; and 4 Molecular Diagnostics Centre, Manchester Royal Infirmary, Manchester, United Kingdom Investigation of 3 families with bleeding symptoms demonstrated a defect in the collagen-binding activity of von Willebrand factor (VWF) in association with a normal VWF multimeric pattern. Genetic analysis showed affected persons to be heterozygous for mutations in the A3 domain of VWF: S1731T, W1745C, and S1783A. One person showed compound heterozygosity for W1745C and R760H. W1745C and S1783A have not been reported previously. The mutations were reproduced by site-directed mutagenesis and mutant VWF expressed in HEK293T cells. Collagen-binding activity measured by immunosorbent assay varied according to collagen type: W1745C and S1783A were associated with a pronounced binding defect to both type I and type III collagen, whereas the principal abnormality in S1731T patients was a reduction in binding to type I collagen only. The multimer pattern and distribution of mutant proteins were indistinguishable from wild-type recombinant VWF, confirming that the defect in collagen binding resulted from the loss of affinity at the binding site and not impairment of high-molecular-weight multimer formation. Our findings demonstrate that mutations causing an abnormality in the binding of VWF to collagen may contribute to clinically significant bleeding symptoms. We propose that isolated collagen-binding defects are classified as a distinct subtype of von Willebrand disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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