Mutation and haplotype analyses of the MUT gene in Japanese patients with methylmalonic acidemia
Mutation and haplotype analyses of the MUT gene in Japanese patients with methylmalonic acidemia
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DOI：
10.1007/s10038-006-0077-2
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发表时间：
2007-01-01
影响因子：
3.5
通讯作者：
Tsuchiya, Shigeru
中科院分区：
文献类型：
--
作者：
Sakamoto, Osamu;Ohura, Toshihiro;Tsuchiya, Shigeru
甲基丙二酸血症（MMA）是由L-甲基丙二酰辅酶A（MCM）活性缺乏引起的，MCM是一种维生素B12（或钴胺素，Cbl）依赖性酶。脱辅基酶缺陷型MMA（mut MMA）是由核基因MUT突变引起的。大多数MUT突变被认为是私人的或仅限于少数谱系。我们的研究小组通过对29例突变型MMA患者进行突变和单体型分析，阐明了日本突变型MMA患者的突变谱。序列分析确定了95%（55/58）的疾病等位基因突变。5个突变相对频繁（p.E117X、c.385 + 5G > A、p.R369H、p.L494X和p.R727X），4个是新突变（p.M1V、c.753_753 + 5delGGTATA、c.1560G > C和c.2098_2099delAT）。单倍型分析表明，除了p.R369H之外，所有常见的突变都是通过奠基者效应传播的。在本研究和既往研究中调查的46例日本患者中，76%（70/92）的突变位于外显子2、6、8和13。这一发现--日本突变MMA患者中的大多数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相反。
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. Our group elucidated the spectrum of mutations of Japanese mut MMA patients by performing mutation and haplotype analyses in 29 patients with mut MMA. 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 + 5delGGTATA, c.1560G > C, and c.2098_2099delAT). Haplotype analysis suggested that all of the frequent mutations, with the exception of 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 2, 6, 8, and 13. This finding - that a limited number of mutations account for most of the mutations in Japanese mut MMA patients - is in contrast with results of a previous study in Caucasian patients.