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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. © 2018 Wiley Periodicals, Inc.


Concetta Altamura, Sabrina Lucchiari, Dalila Sahbani, Gianna Ulzi, Giacomo P Comi, Paola D'Ambrosio, Roberta Petillo, Luisa Politano, Liliana Vercelli, Tiziana Mongini, Maria Teresa Dotti, Rosanna Cardani, Giovanni Meola, Mauro Lo Monaco, Emma Matthews, Michael G Hanna, Maria Rosaria Carratù, Diana Conte, Paola Imbrici, Jean-François Desaphy. 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. Human mutation. 2018 Sep;39(9):1273-1283

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PMID: 29935101

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