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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans
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Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans

机译：胆碱乙酰基转移酶突变引起与人类间歇性呼吸暂停相关的肌无力综合征

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摘要

Choline acetyltransferase (ChAT: EC 2.3.1.6) catalyzes the reversible synthesis of acetylcholine (ACh) from acetyl CoA and choline at cholinergic synapses. Mutations in genes encoding ChAT affecting motility exist in Caenorhabditis elegans and Drosophila. but no CHAT mutations have been observed in humans to date. Here we report that mutations in CHAT cause a congenital myasthenic syndrome associated with frequently fatal episodes of apnea (CMS-EA). Studies of the neuromuscular junction in this disease show a stimulation- dependent decrease of the amplitude of the miniature endplate potential and no deficiency of the ACh receptor. These findings point to a defect in ACh resynthesis or vesicular filling and to CHAT as one of the candidate genes. Direct sequencing of CHAT reveals 10 reces- sive mutations in five patients with CMS-EA. One mutation (523insCC) is a frameshifting null mutation. Three mutations (l305T, R420C, and E441K) markedly reduce CHAT expression in COS cells. Kinetic studies of nine bacterially expressed CHAT mutants demonstrate that one mutant (E441K) lacks catalytic activity, and eight mutants (L210P. P211A. I305T. R420C. R482G, S498L, V506L, and R560H) have signifi- cantly impaired catalytic efficiencies.
机译：胆碱乙酰基转移酶（ChAT：EC 2.3.1.6）催化胆碱能突触由乙酰辅酶A和胆碱可逆合成乙酰胆碱（ACh）。秀丽隐杆线虫和果蝇中存在编码影响运动能力的ChAT的基因突变。但迄今为止，尚未在人类中发现CHAT突变。在这里我们报告说，CHAT突变会导致与致命性呼吸暂停发作（CMS-EA）相关的先天性肌无力综合征。对这种疾病的神经肌肉接头的研究表明，微型终板电位的振幅与刺激有关，而ACh受体没有缺陷。这些发现表明ACh重新合成或囊泡充盈存在缺陷，并且CHAT作为候选基因之一。 CHAT的直接测序揭示了5例CMS-EA患者的10个再发突变。一个突变（523insCC）是移码无效突变。三个突变（1305T，R420C和E441K）显着降低COS细胞中的CHAT表达。对9种细菌表达的CHAT突变体的动力学研究表明，一个突变体（E441K）缺乏催化活性，而8个突变体（L210P。P211A。I305T。R420C。R482G，S498L，V506L和R560H）大大削弱了催化效率。

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