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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 (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 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 Dahlback, B. Search for Related Content PubMed PubMed Citation Articles by Steen, M. Articles by Dahlback, B. Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Submitted January 15, 2003 Accepted March 31, 2003 Factor V New Brunswick: Ala221Val associated with FV deficiency reproduced in vitro and functionally characterized Marten Steen, Maria Miteva, Bruno O Villoutreix, Tomio Yamazaki, and Bjorn Dahlback* Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, Malmo, Sweden Inserm, Unite 428, University of Paris V, Paris, France * Corresponding author; email: bjorn.dahlback{at}klkemi.mas.lu.se. 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, A221V, assigned as FV New Brunswick. To elucidate the molecular pathology associated with the A221V substitution, the mutation was recreated in a recombinant system, together with three FV mutants (A221G, E275Q and C220A/C301A) designed to help explain the A221V phenotype. The expression pattern was analyzed by pulse-chase experiments and a FV-specific ELISA, the results suggesting the A221V 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 A221V mutation did not affect the FXa-cofactor function, nor did it interfere with the APC-mediated down regulation of FVa activity. However, FV New Brunswick demonstrated reduced stability at 37°C, due to increased rate of dissociation of light and heavy chains of FVa. In conclusion, this in vitro study of FV New Brunswick suggests the A221V mutation not to impair synthesis and expression of procoagulant activity, indicating overall proper folding of the mutant molecule. Rather, the A221V 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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