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

甲基丙二酸血症是由维生素B12(或钴胺，Cbl)依赖的L甲基丙二酰辅酶A变位酶(MCM)活性不足引起的。脱氧核酶缺陷型MMA(Mut MMA)是由核内突变引起的。吉恩·穆特。大多数MUT突变被认为是私人的或仅限于少数家系。1)在本研究中，突变。并对29例MUT MMA患者进行了单倍型分析。序列分析发现，95%(55/58)的疾病等位基因发生了突变。比较常见的突变有5个(p.E117X、c.385+5G&gt；A、p.R369H、p.L494X和p.R727X)和4个新突变(p.M1V、c.753_753+5de1GGTATA、c.1560G&gt；C和c.2098_2099delAT)。单倍型分析表明，除p.R369H外，其余突变均由创始人效应传播。在目前和以前的研究中调查的46例日本患者中，76%(70/92)的突变位于第2、6、8和13外显子。这一发现表明，日本MUT MMA的大部分突变是由有限数量的突变引起的。与之前在高加索患者中进行的研究结果形成对比。2)对19例良性AMA患者进行序列分析。虽然对MUT、MC-PE、MMAA、MMAB和MMACHC等基因进行了分析，但未发现突变。良性MMA的发病机制尚不清楚。

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.