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Prepublished online as a Blood First Edition Paper on April 24, 2003; DOI 10.1182/blood-2003-01-0116. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-01-0116v1 102/4/1316    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Steen, M. Articles by Dahlbäck, B. Search for Related Content PubMed PubMed Citation Articles by Steen, M. Articles by Dahlbäck, B. Related Collections Hemostasis, Thrombosis, and Vascular Biology Gene Expression Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 August 2003, Vol. 102, No. 4, pp. 1316-1322 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Factor V New Brunswick: Ala221Val associated with FV deficiency reproduced in vitro and functionally characterized Mårten Steen, Maria Miteva, Bruno O. Villoutreix, Tomio Yamazaki, and Björn Dahlbäck From the Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, The Wallenberg Laboratory, University Hospital, Malmö, Sweden; and Institut National de la Santé et de la Recherche Médicale (INSERM) U428, University of Paris V, France. Factor V (FV) deficiency, also known as parahemophilia, is a rare bleeding disorder. Herein we investigate the first reported missense mutation associated with FV deficiency, Ala221Val, assigned as FV New Brunswick. To elucidate the molecular pathology associated with the Ala221Val substitution, the mutation was recreated in a recombinant system together with 3 FV mutants (Ala221Gly, Glu275Gln, and Cys220Ala/Cys301Ala) designed to help explain the Ala221Val phenotype. The expression pattern was analyzed by pulse-chase experiments and an FV-specific enzyme-linked immunosorbent assay (ELISA), the results suggesting the Ala221Val mutation not to interfere with the synthesis or secretion. The functional properties of the recombinant FV New Brunswick were evaluated in both plasma clotting and purified systems. The Ala221Val mutation did not affect the factor Xa (FXa) cofactor function; nor did it interfere with the activated protein C (APC)–mediated down-regulation of activated FV (FVa) activity. However, FV New Brunswick demonstrated reduced stability at 37°C due to an increased rate of dissociation of light and heavy chains of FVa. In conclusion, this in vitro study of FV New Brunswick suggests the Ala221Val mutation not to impair synthesis and expression of procoagulant activity, indicating overall proper folding of the mutant molecule. Rather, the Ala221Val substitution appears to interfere with the stability of the activated FVa mutant, the reduced stability possibly explaining the deficiency symptoms associated with the mutation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Novel functional defect in factor V deficiency William H. Kane Blood 2003 102: 1150-1151. [Full Text] [PDF] This article has been cited by other articles: P. M. Mannucci, S. Duga, and F. Peyvandi Recessively inherited coagulation disorders Blood, September 1, 2004; 104(5): 1243 - 1252. [Abstract] [Full Text] [PDF]

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