CONGENITAL MYASTHENIC SYNDROME CAUSED BY PROLONGED ACETYLCHOLINE-RECEPTOR CHANNEL OPENINGS DUE TO A MUTATION IN THE M2 DOMAIN OF THE EPSILON-SUBUNIT
CONGENITAL MYASTHENIC SYNDROME CAUSED BY PROLONGED ACETYLCHOLINE-RECEPTOR CHANNEL OPENINGS DUE TO A MUTATION IN THE M2 DOMAIN OF THE EPSILON-SUBUNIT
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DOI：
10.1073/pnas.92.3.758
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发表时间：
1995-01-31
影响因子：
11.1
通讯作者：
ENGEL, AG
中科院分区：
文献类型：
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作者：
OHNO, K;HUTCHINSON, DO;ENGEL, AG
在患有严重终板肌病的先天性肌无力综合征中，膜片钳研究显示乙酰胆碱受体（AChR）通道开放时间明显延长。 AChR 亚基基因的分子遗传学分析表明，ε 亚基基因的外显子 8 中的核苷酸 790 处存在杂合腺苷至胞嘧啶颠倒，预测密码子 264 处的脯氨酸将取代苏氨酸，并且编码 (α、β、δ 和 ε 亚基的基因的整个编码序列中没有其他突变。 在人胚胎肾成纤维细胞系中表达的基因工程突变体 AChR 在激动剂存在下也表现出显着延长的开放时间，甚至在激动剂不存在的情况下也开放。 ε 亚基中的 Thr-264 --> Pro 突变涉及通道孔内衬的 M2 结构域中的高度保守残基，并且可能会破坏假定的 M2 α 螺旋。我们的研究结果表明，单一 关键位点的突变可以极大地改变 AChR 通道动力学，导致先天性肌无力综合征。这一观察结果提出了一种可能性，即涉及其他配体门控通道亚基的突变也可能存在，并且是各种其他神经或精神疾病的基础。
In a congenital myasthenic syndrome with a severe endplate myopathy, patch-clamp studies revealed markedly prolonged acetylcholine receptor (AChR) channel openings. Molecular genetic analysis of AChR subunit genes demonstrated a heterozygous adenosine-to-cytosine transversion at nucleotide 790 in exon 8 of the epsilon-subunit gene, predicting substitution of proline for threonine at codon 264 and no other mutations in the entire coding sequences of genes encoding the (alpha, beta, delta, and epsilon subunits. Genetically engineered mutant AChR expressed in a human embryonic kidney fibroblast cell line also exhibited markedly prolonged openings in the presence of agonist and even opened in its absence. The Thr-264 --> Pro mutation in the epsilon subunit involves a highly conserved residue in the M2 domain lining the channel pore and is likely to disrupt the putative M2 alpha-helix. Our findings indicate that a single mutation at a critical site can greatly alter AChR channel kinetics, leading to a congenital myasthenic syndrome. This observation raises the possibility that mutations involving subunits of other ligand-gated channels may also exist and be the basis of various other neurologic or psychiatric disorders.