Mutations in dominant human myotonia congenita drastically alter the voltage dependence of the CIC-1 chloride channel
Mutations in dominant human myotonia congenita drastically alter the voltage dependence of the CIC-1 chloride channel
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DOI：
10.1016/0896-6273(95)90023-3
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发表时间：
1995-12-01
期刊：
影响因子：
16.2
通讯作者：
Jentsch, TJ
中科院分区：
文献类型：
--
作者：
Pusch, M;Steinmeyer, K;Jentsch, TJ
常染色体显性先天性肌强直（汤姆森病）是由肌肉氯离子通道CIC-1突变引起的。在受影响的家族中发现的几个点突变（1290M, R317Q， P480L和Q552R）在突变/WT异聚物通道中显著地将门控转移到正电压，并且，当可测量时，在突变的同聚物中甚至更多。这些通道不能再促进动作电位的复极化，这就充分解释了为什么它们会导致显性肌强直。大多数替换的异亮氨酸在位置290移位门控向正电压。突变体/WT异聚物可以通过重复去极化部分激活，提示在缩短肌强直运行中起作用。值得注意的是，影响相邻残基（E291K）的人类突变是完全隐性的。门控电压依赖性的大位移可能是显性先天性肌强直的许多突变所共有的。
Autosomal dominant myotonia congenita (Thomsen's disease) is caused by mutations in the muscle chloride channel CIC-1. Several point mutations found in affected families (1290M, R317Q, P480L, and Q552R) dramatically shift gating to positive voltages in mutant/WT heterooligomeric channels, and, when measurable, even more so in mutant homooligomers. These channels can no longer contribute to the repolarization of action potentials, fully explaining why they cause dominant myotonia. Most replacements of the isoleucine at position 290 shift gating toward positive voltages. Mutant/WT heterooligomers can be partially activated by repetitive depolarizations, suggesting a role in shortening myotonic runs. Remarkably, a human mutation affecting an adjacent residue (E291K) is fully recessive. Large shifts in the voltage dependence of gating may be common to many mutations in dominant myotonia congenita.