Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor epsilon subunit
Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor epsilon subunit
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DOI：
10.1016/s0896-6273(00)80289-5
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发表时间：
1996-07-01
期刊：
影响因子：
16.2
通讯作者：
Engel, AG
中科院分区：
文献类型：
--
作者：
Ohno, K;Wang, HL;Engel, AG
我们描述了导致肌无力综合征的乙酰胆碱受体（AChR）低亲和力快速通道疾病的遗传和动力学缺陷。在两名无关的患者中，微型终板 (EP) 电位非常小，但 EP AChR 密度和 EP 超微结构正常，膜片钳研究表明 AChR 通道事件不频繁、ACh 占用期间通道重新开放减少以及对 ACh 脱敏的抵抗。每个患者都有两个异等位基因 AChR epsilon 亚基基因突变：常见的 epsilon P121L 突变、信号肽突变 (epsilon G-8R)（患者 1）和糖基化共有位点突变 (epsilon S143L)（患者 2）。 HEK 成纤维细胞中的 AChR 表达在 epsilon P121L 中正常，但在其他突变中显着降低。因此，epsilon P121L 定义了临床表型。对工程化 epsilon P121L AChR 的研究表明，通道开放率显着降低，静息状态对 ACh 的亲和力几乎没有变化，但开放通道和脱敏状态的亲和力降低。
We describe the genetic and kinetic defects for a low-affinity fast channel disease of the acetylcholine receptor (AChR) that causes a myasthenic syndrome. In two unrelated patients with very small miniature end plate (EP) potentials, but with normal EP AChR density and normal EP ultrastructure, patch-clamp studies demonstrated infrequent AChR channel events, diminished channel reopenings during ACh occupancy, and resistance to desensitization by ACh. Each patient had two heteroallelic AChR epsilon subunit gene mutations: a common epsilon P121L mutation, a signal peptide mutation (epsilon G-8R) (patient 1), and a glycosylation consensus site mutation (epsilon S143L) (patient 2). AChR expression in HEK fibroblasts was normal with epsilon P121L but was markedly reduced with the other mutations. Therefore, epsilon P121L defines the clinical phenotype. Studies of the engineered epsilon P121L AChR revealed a markedly decreased rate of channel opening, little change in affinity of the resting state for ACh, but reduced affinity of the open channel and desensitized states.