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

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. We provide clinical and patch‐clamp analysis of ClC‐1 chloride channel mutations causing Myotonia Congenita and located in the poorly characterized cytosolic C‐terminal domain. The dysfunctions of mutant channels well correlated with the phenotypes. Clusters of ClC‐1 mutations within CBS2 and C‐terminal peptide sub‐domains appeared to share similar functional defect. This study improves our understanding of the mechanisms underlying MC and of the role of the C‐terminal region in ClC‐1 function, providing information to develop new antimyotonic drugs.