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.
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 / C. Altamura, S. Lucchiari, D. Sahbani, G. Ulzi, G.P. Comi, P. D'Ambrosio, R. Petillo, L. Politano, L. Vercelli, T. Mongini, M.T. Dotti, R. Cardani, G. Meola, M. Lo Monaco, E. Matthews, M.G. Hanna, M.R. Carratù, D. Conte, P. Imbrici, J. Desaphy. - In: HUMAN MUTATION. - ISSN 1059-7794. - 39:9(2018 Sep), pp. 1273-1283.
|Titolo:||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|
|Parole Chiave:||C-terminal; ClC-1; myotonia congenita; patch clamp; Genetics; Genetics (clinical)|
|Settore Scientifico Disciplinare:||Settore MED/26 - Neurologia|
|Data di pubblicazione:||set-2018|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1002/humu.23581|
|Appare nelle tipologie:||01 - Articolo su periodico|