Screening of gene mutations for methylmalonic acidemia and serch for responsible gene of benign-type methylmalonic acidemia

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Methylmalonic acidemia (MMA) is caused by a deficiency in the activity of L-methylmalonyl-CoA mutase (MCM), a vitamin B12 (or cobalamin, Cbl)-dependent enzyme. Apoenzyme-deficient MMA (mut MMA) results from mutations in the nuclear. gene MUT. Most of the MUT mutations are thought to be private or restricted to only a few pedigrees. 1) In this study, mutation. and haplotype analyses in 29 patients with mut MMA were performed. A sequence analysis identified mutations in 95% (55/58) of the disease alleles. Five mutations were relatively frequent (p.E117X, c.385+5G>A, p.R369H, p.L494X, and p.R727X) and four were novel (p.M1V, c.753_753+5de1GGTATA, c.1560G>C, and c.2098_2099delAT). Haplotype analysis suggested that all of the frequent mutations except p.R369H were spread by the founder effect. Among 46 Japanese patients investigated in the present and previous studies, 76% (70/92) of the mutations were located in exons of 2, 6, 8, and 13. This finding, a limited number of mutations accounting for most of the mutations in Japanese mut MMA. Patients, contrasts with the result of a previous study in Caucasian patients. 2) In 19 patients with benign-type AMA, sequence analysis was performed. Although the genes such as MUT,, MC-PE, MMAA, MMAB, and MMACHC were analyzed, no mutation was found. The mechanism of benign-type MMA is still unknown.