%X Myotonia congenita (MC) is a skeletalâ€muscle hyperexcitability disorder caused by lossâ€ofâ€function mutations in the ClCâ€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 Câ€terminal domain. In this study, we characterized, through patch clamp, seven ClCâ€1 mutations identified in patients affected by MC of various severities and located in the Câ€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 Câ€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 ClCâ€1 mutations within CBS2 and Câ€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 ClCâ€1 function. This study improves our understanding of the mechanisms underlying MC, sheds light on the role of the Câ€terminal region in ClCâ€1 function, and provides information to develop new antimyotonic drugs. %L discovery10067472 %I WILEY %O This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. %J Human Mutation %A C Altamura %A S Lucchiari %A D Sahbani %A G Ulzi %A GP Comi %A P D'Ambrosio %A R Petillo %A L Politano %A L Vercelli %A T Mongini %A MT Dotti %A R Cardani %A G Meola %A M Lo Monaco %A E Matthews %A MG Hanna %A MR Carratù %A D Conte %A P Imbrici %A J-F Desaphy %V 39 %P 1273-1283 %K Câ€terminal, ClCâ€1, myotonia congenita, patch clamp %T The analysis of myotonia congenita mutations discloses functional clusters of amino acids within the CBS2 domain and the Câ€terminal peptide of the ClCâ€1 channel %N 9 %D 2018