The analysis of myotonia congenita mutations discloses functional clusters of amino acids within the CBS2 domain and the C-terminal peptide of the ClC-1 channel
The analysis of myotonia congenita mutations discloses functional clusters of amino acids within the CBS2 domain and the C-terminal peptide of the ClC-1 channel
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DOI：
10.1002/humu.23581
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发表时间：
2018-09-01
期刊：
影响因子：
3.9
通讯作者：
Desaphy, Jean-Francois
中科院分区：
文献类型：
--
作者：
Altamura, Concetta;Lucchiari, Sabrina;Desaphy, Jean-Francois
先天性肌强直 (MC) 是一种由 ClC-1 氯通道功能丧失突变引起的骨骼肌过度兴奋性疾病。突变分散在通道蛋白的整个序列中，其中 30 多个突变位于特征不明的胞质 C 端结构域。在这项研究中，我们通过膜片钳鉴定了在不同严重程度的 MC 患者中发现的 7 个 ClC-1 突变，这些突变位于 C 末端区域。 p.Val829Met、p.Thr832Ile、p.Val851Met、p.Gly859Val 和 p.Leu861Pro 突变位于 CBS2 结构域，而 p.Pro883Thr 和 p.Val947Glu 位于 C 末端肽中。我们发现突变通道的功能特性与受影响个体的临床表型相关。此外，我们定义了 CBS2 和 C 端肽亚域内的 ClC-1 突变簇，它们具有相同的功能缺陷：829 和 835 残基之间以及残基 883 之间的突变诱导电压依赖性的改变，851 和 859 残基之间以及残基 947 之间的突变诱导氯电流减少，而 861 残基上的突变在 ClC-1 功能中没有显示明显的变化。这项研究提高了我们对 MC 机制的理解，阐明了 C 末端区域在 ClC-1 功能中的作用，并为开发新的抗肌强直药物提供了信息。
Myotonia congenita (MC) is a skeletal-muscle hyperexcitability disorder caused by loss-of-function mutations in the ClC-1 chloride channel. Mutations are scattered over the entire sequence of the channel protein, with more than 30 mutations located in the poorly characterized cytosolic C-terminal domain. In this study, we characterized, through patch clamp, seven ClC-1 mutations identified in patients affected by MC of various severities and located in the C-terminal region. The p.Val829Met, p.Thr832Ile, p.Val851Met, p.Gly859Val, and p.Leu861Pro mutations reside in the CBS2 domain, while p.Pro883Thr and p.Val947Glu are in the C-terminal peptide. We showed that the functional properties of mutant channels correlated with the clinical phenotypes of affected individuals. In addition, we defined clusters of ClC-1 mutations within CBS2 and C-terminal peptide subdomains that share the same functional defect: mutations between 829 and 835 residues and in residue 883 induced an alteration of voltage dependence, mutations between 851 and 859 residues, and in residue 947 induced a reduction of chloride currents, whereas mutations on 861 residue showed no obvious change in ClC-1 function. This study improves our understanding of the mechanisms underlying MC, sheds light on the role of the C-terminal region in ClC-1 function, and provides information to develop new antimyotonic drugs.