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Blood, 15 June 2008, Vol. 111, No. 12, pp. 5592-5600. Prepublished online as a Blood First Edition Paper on April 7, 2008; DOI 10.1182/blood-2007-10-113951. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-10-113951v1 111/12/5592    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 Zhang, B. Articles by Ginsburg, D. PubMed PubMed Citation Articles by Zhang, B. Articles by Ginsburg, D. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Genotype-phenotype correlation in combined deficiency of factor V and factor VIII Bin Zhang1, Marta Spreafico2, Chunlei Zheng1, Angela Yang3, Petra Platzer1, Michael U. Callaghan4, Zekai Avci5, Namik Ozbek5, Johnny Mahlangu6, Tabitha Haw6, Randal J. Kaufman7, Kandice Marchant8, Edward G. D. Tuddenham9, Uri Seligsohn10, Flora Peyvandi2, and David Ginsburg3 1 Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, OH; 2 A. Bianchi Bonomi Hemophilia and Thrombosis Centre, University of Milan and Department of Medicine and Medical Specialties, Luigi Villa Foundation, Istituti di ricovero e cura a carattere scientifico (IRCCS) Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Milan, Italy; 3 Life Sciences Institute, Departments of Internal Medicine and Human Genetics, University of Michigan, Ann Arbor; 4 Children's Hospital of Michigan, Wayne State University, Detroit; 5 Baskent University Faculty of Medicine, Ankara, Turkey; 6 National Health Laboratory Service and the University of the Witwatersrand, Johannesburg, South Africa; 7 Departments of Biological Chemistry and Internal Medicine, University of Michigan, Ann Arbor; 8 Pathology and Lab Medicine Division, Cleveland Clinic Foundation, OH; 9 Haemophilia Centre and Haemostasis Unit, Royal Free Hospital, London, United Kingdom; and 10 Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel-Hashomer, Israel Combined deficiency of factor V and factor VIII (F5F8D) is caused by mutations in one of 2 genes, either LMAN1 or MCFD2. Here we report the identification of mutations for 11 additional F5F8D families, including 4 novel mutations, 2 in MCFD2 and 2 in LMAN1. We show that a novel MCFD2 missense mutation identified here (D81Y) and 2 previously reported mutations (D89A and D122V) abolish MCFD2 binding to LMAN1. Measurement of platelet factor V (FV) levels in 7 F5F8D patients (4 with LMAN1 and 3 with MCFD2 mutations) demonstrated similar reductions to those observed for plasma FV. Combining the current data together with all previous published reports, we performed a genotype-phenotype analysis comparing patients with MCFD2 mutations with those with LMAN1 mutations. A previously unappreciated difference is observed between these 2 classes of patients in the distribution of plasma levels for FV and factor VIII (FVIII). Although there is considerable overlap, the mean levels of plasma FV and FVIII in patients with MCFD2 mutations are significantly lower than the corresponding levels in patients with LMAN1 mutations. No differences in distribution of factor levels are observed by sex. These data suggest that MCFD2 may play a primary role in the export of FV and FVIII from the ER, with the impact of LMAN1 mediated indirectly through its interaction with MCFD2. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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