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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 (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 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 Citing Articles via Google Scholar Google Scholar Articles by Zhang, B. Articles by Ginsburg, D. Search for Related Content PubMed PubMed Citation Articles by Zhang, B. Articles by Ginsburg, D. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 11, 2007 Accepted March 31, 2008 Genotype-phenotype correlation in combined deficiency of factor V and factor VIII Bin Zhang*, Marta Spreafico, Chunlei Zheng, Angela Yang, Petra Platzer, Michael U Callaghan, Zekai Avci, Namik Ozbek, Johnny Mahlangu, Tabitha Haw, Randal J Kaufman, Kandice Marchant, EGD Tuddenham, Uri Seligsohn, Flora Peyvandi, and David Ginsburg Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, United States A. Bianchi Bonomi Hemophilia & Thrombosis Centre, Univ of Milan, and Dept of Medicine & Medical Spec, Luigi Villa Foundation, IRCCS Maggiore Hospital, Mangiagalli & Regina Elena Foundation, Milan, Italy Life Sciences Institute, Depts of Internal Medicine and Human Genetics, University of Michigan, Ann Arbor, MI, United States Children's Hospital of Michigan, Wayne State University, Detroit, MI, United States Department of Pediatric Hematology, Baskent University Faculty of Medicine, Ankara, Turkey National Health Laboratory Service, and University of the Witwatersrand, Johannesburg, South Africa Departments of Biological Chemistry and Internal Medicine, University of Michigan, Ann Arbor, MI, United States Pathology and Lab Medicine Division, Cleveland Clinic Foundation, Cleveland, OH, United States Hemophilia Centre and Haemostasis Unit, Royal Free Hospital, London, United Kingdom Institute of Thrombosis & Hemostasis, Sheba Medical Center, Tel-Hashomer, Israel Life Sciences Institute, Dept of Internal Medicine and Human Genetics, University of Michigan, Ann Arbor, MI, United States * Corresponding author; email: zhangb{at}ccf.org. Combined deficiency of factor V and factor VIII (F5F8D) is caused by mutations in one of two 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 to those with LMAN1 mutations. A previously unappreciated difference is observed between these two 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 gender. 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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