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Methylmalonic aciduria and homocystinuria, cblC type (OMIM 277400), is the most common inborn error of vitamin B 12 (cobalamin) metabolism, with about 250 known cases. Affected individuals have developmental, hematological, neurological, metabolic, ophthalmologic and dermatologic clinical findings 1 . Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood 2 . The cblC locus was mapped to chromosome region 1p by linkage analysis 3 . 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.

Vitamin B12 (cobalamin, Cbl) is required as a cofactor for two human enzymes: methylmalonyl-CoA mutase (MCM) and methionine synthase (MS). Fibroblasts from patients with inborn errors of cobalamin metabolism have been classified into nine distinct complementation classes ( cblA-cblH and mut). Previous studies have shown that cobalamin binds MCM in mitochondria and MS in the cytosol. Cobalamin binding patterns were analyzed in crude mitochondrial fractions obtained from normal and mutant fibroblasts. Crude mitochondrial fractions from wildtype fibroblasts confirmed that the majority of [57Co]Cbl eluted with MCM. However, in six of the nine disorders, at least one previously unidentified mitochondrial cobalamin binding protein was observed to bind [57Co]Cbl. The proportion of [57Co]Cbl that binds, is increased when a deficiency in either adenosylcobalamin synthesis or utilization prevents binding to MCM. Furthermore, unique cobalamin binding profiles emerged, demonstrating how known mutations in these patients affect cobalamin binding to accessory proteins.