Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2
| Autor: | Paula L. Bockenstedt, Arlette Ruiz-Saez, Randal J. Kaufman, Katharine A. Downes, Gustavo Jarchum, Marian Olpinski, Norma B. de Bosch, Flora Peyvandi, Beth McGee, Hugo Guglielmone, Salvador Minoldo, Bernard Chatelain, Wolfgang Sperl, Jennifer S. Yamaoka, William C. Nichols, Bin Zhang, David Ginsburg, Edward G. D. Tuddenham |
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| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
Factor V Deficiency
Immunology Blotting Western DNA Mutational Analysis Mutation Missense Vesicular Transport Proteins Golgi Apparatus medicine.disease_cause Endoplasmic Reticulum Hemophilia A Biochemistry Hemostasis Thrombosis and Vascular Biology medicine Missense mutation Humans Point Mutation RNA Messenger Allele Gene Alleles Genetics Mutation Factor VIII biology Point mutation Factor V Membrane Proteins Cell Biology Hematology Molecular biology Blot Protein Transport Mannose-Binding Lectins Amino Acid Substitution Multiprotein Complexes biology.protein Carrier Proteins |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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