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Blood, 1 March 2006, Vol. 107, No. 5, pp. 1903-1907. Prepublished online as a Blood First Edition Paper on January 31, 2006; DOI 10.1182/blood-2005-09-3620. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-09-3620v1 2005-09-3620v2 107/5/1903    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 Zhang, B. Articles by Ginsburg, D. Search for Related Content PubMed PubMed Citation Articles by Zhang, B. Articles by Ginsburg, D. Related Collections Hemostasis, Thrombosis, and Vascular Biology Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2 Bin Zhang, Beth McGee, Jennifer S. Yamaoka, Hugo Guglielmone, Katharine A. Downes, Salvador Minoldo, Gustavo Jarchum, Flora Peyvandi, Norma B. de Bosch, Arlette Ruiz-Saez, Bernard Chatelain, Marian Olpinski, Paula Bockenstedt, Wolfgang Sperl, Randal J. Kaufman, William C. Nichols, Edward G. D. Tuddenham, and David Ginsburg From the Life Sciences Institute, Departments of Internal Medicine, Human Genetics, Biological Chemistry, and Howard Hughes Medical Institute, University of Michigan, Ann Arbor; Sercicio de Hematología, Clínica-Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI)-Consejo Nacional de Investigaciones Cientificas y Técnias (CONICET), National Córdoba University, Argentina; University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH; Bonomi Haemophilia and Thrombosis Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Maggiore Hospital and University of Milan, Italy; Centro Nacional de Hemofilia, Banco Municipal de Sangre, Caracas, Venezuela; University Hospital of Mont-Godinne, Université Catholique de Louvain, Louvain, Belgium; Institute of Nursing and Midwifery, University of Rzeszow, Poland; Department of Pediatrics, Private Medical University, Salzburg, Austria; Cincinnati Children's Hospital Medical Center, OH; and Medical Research Council (MRC) Clinical Sciences Center, Imperial College, London, United Kingdom. Mutations in LMAN1 (ERGIC-53) or MCFD2 cause combined deficiency of factor V and factor VIII (F5F8D). LMAN1 and MCFD2 form a protein complex that functions as a cargo receptor ferrying FV and FVIII from the endoplasmic reticulum to the Golgi. In this study, we analyzed 10 previously reported and 10 new F5F8D families. Mutations in the LMAN1 or MCFD2 genes accounted for 15 of these families, including 3 alleles resulting in no LMAN1 mRNA accumulation. Combined with our previous reports, we have identified LMAN1 or MCFD2 mutations as the causes of F5F8D in 71 of 76 families. Among the 5 families in which no mutations were identified, 3 were due to misdiagnosis, with the remaining 2 likely carrying LMAN1 or MCFD2 mutations that were missed by direct sequencing. Our results suggest that mutations in LMAN1 and MCFD2 may account for all cases of F5F8D. Immunoprecipitation and Western blot analysis detected a low level of LMAN1-MCFD2 complex in lymphoblasts derived from patients with missense mutations in LMAN1 (C475R) or MCFD2 (I136T), suggesting that complete loss of the complex may not be required for clinically significant reduction in FV and FVIII. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B. Zhang, M. Spreafico, C. Zheng, A. Yang, P. Platzer, M. U. Callaghan, Z. Avci, N. Ozbek, J. Mahlangu, T. Haw, et al. Genotype-phenotype correlation in combined deficiency of factor V and factor VIII Blood, June 15, 2008; 111(12): 5592 - 5600. [Abstract] [Full Text] [PDF] N. Kawasaki, Y. Ichikawa, I. Matsuo, K. Totani, N. Matsumoto, Y. Ito, and K. Yamamoto The sugar-binding ability of ERGIC-53 is enhanced by its interaction with MCFD2 Blood, February 15, 2008; 111(4): 1972 - 1979. [Abstract] [Full Text] [PDF] B. Nyfeler, Y. Kamiya, F. Boehlen, K. Yamamoto, K. Kato, P. de Moerloose, H.-P. Hauri, and M. Neerman-Arbez Deletion of 3 residues from the C-terminus of MCFD2 affects binding to ERGIC-53 and causes combined factor V and factor VIII deficiency Blood, February 1, 2008; 111(3): 1299 - 1301. [Abstract] [Full Text] [PDF] V. M. Olkkonen and E. Ikonen When intracellular logistics fails - genetic defects in membrane trafficking J. Cell Sci., December 15, 2006; 119(24): 5031 - 5045. [Abstract] [Full Text] [PDF]

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