Nature Genetics 38, 93 - 100 (2006)
Published online: 27 November 2005; Corrected online: 30 June 2006 | doi:10.1038/ng1683
There is an Erratum (August 2006) associated with this Letter.
Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC typeJordan P Lerner-Ellis1, 2, Jamie C Tirone1, 2, Peter D Pawelek3, Carole Doré4, Janet L Atkinson5, David Watkins1, 2, Chantal F Morel1, 2, T Mary Fujiwara1, 2, Emily Moras1, 2, Angela R Hosack2, Gail V Dunbar2, Hana Antonicka1, 6, Vince Forgetta4, C Melissa Dobson7, Daniel Leclerc1, 2, Roy A Gravel7, Eric A Shoubridge1, 6, James W Coulton3, Pierre Lepage4, Johanna M Rommens5, Kenneth Morgan1, 2
& David S Rosenblatt1, 21
Department of Human Genetics, McGill University, Montreal, Quebec, Canada, H3G 1B1. 2
Division of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada, H3G 1A4. 3
Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada, H3A 2B4. 4
McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada, H3A 1A4. 5
Department of Molecular and Medical Genetics, University of Toronto and Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario, Canada, M5G 1X8. 6
Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada, H3A 2B4. 7
Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
Correspondence should be addressed to David S Rosenblatt david.rosenblatt@mcgill.ca Methylmalonic aciduria and homocystinuria, cblC type (OMIM 277400), is the most common inborn error of vitamin B12 (cobalamin) metabolism, with about 250 known cases. Affected individuals have developmental, hematological, neurological, metabolic, ophthalmologic and dermatologic clinical findings1. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood2. The cblC locus was mapped to chromosome region 1p by linkage analysis3. We refined the chromosomal interval using homozygosity mapping and haplotype analyses and identified the MMACHC gene. In 204 individuals, 42 different mutations were identified, many consistent with a loss of function of the protein product. One mutation, 271dupA, accounted for 40% of all disease alleles. Transduction of wild-type MMACHC into immortalized cblC fibroblast cell lines corrected the cellular phenotype. Molecular modeling predicts that the C-terminal region of the gene product folds similarly to TonB, a bacterial protein involved in energy transduction for cobalamin uptake.
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