|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
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.
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2From 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.
This article has been cited by other articles:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||||
 |
 |
 |
 |
 |
 |
 |
 |
||||
| |||||||||||
| Copyright © 2006 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
