TITLE

Myotonia Congenita Mutation Enhances the Degradation of Human CLC-1 Chloride Channels

AUTHOR(S)
Lee, Ting-Ting; Zhang, Xiao-Dong; Chuang, Chao-Chin; Chen, Jing-Jer; Chen, Yi-An; Chen, Shu-Ching; Chen, Tsung-Yu; Tang, Chih-Yung
PUB. DATE
February 2013
SOURCE
PLoS ONE;Feb2013, Vol. 8 Issue 2, p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Myotonia congenita is a hereditary muscle disorder caused by mutations in the human voltage-gated chloride (Cl−) channel CLC-1. Myotonia congenita can be inherited in an autosomal recessive (Becker type) or dominant (Thomsen type) fashion. One hypothesis for myotonia congenita is that the inheritance pattern of the disease is determined by the functional consequence of the mutation on the gating of CLC-1 channels. Several disease-related mutations, however, have been shown to yield functional CLC-1 channels with no detectable gating defects. In this study, we have functionally and biochemically characterized a myotonia mutant: A531V. Despite a gating property similar to that of wild-type (WT) channels, the mutant CLC-1 channel displayed a diminished whole-cell current density and a reduction in the total protein expression level. Our biochemical analyses further demonstrated that the reduced expression of A531V can be largely attributed to an enhanced proteasomal degradation as well as a defect in protein trafficking to surface membranes. Moreover, the A531V mutant protein also appeared to be associated with excessive endosomal-lysosomal degradation. Neither the reduced protein expression nor the diminished current density was rescued by incubating A531V-expressing cells at 27°C. These results demonstrate that the molecular pathophysiology of A531V does not involve anomalous channel gating, but rather a disruption of the balance between the synthesis and degradation of the CLC-1 channel protein.
ACCESSION #
87624126

 

Related Articles

  • Molecular mechanisms of ion conduction in CIC-type chloride channels: Lessons from disease-causing mutations. Fahlke, Christoph // Kidney International;Mar2000, Vol. 57 Issue 3, p780 

    Examines the molecular mechanisms of ion conduction in CIC-type chloride channels. Cause of recessive generated myotonia congenita and dominant myotonia; Significance of functional characterization of the naturally occurring mutations; Molecular basis of ion permeation and selection in CIC-type...

  • A Novel Mutation in CLCN1 Associated with Feline Myotonia Congenita. Gandolfi, Barbara; Daniel, Rob J.; O'Brien, Dennis P.; Guo, Ling T.; Youngs, Melanie D.; Leach, Stacey B.; Jones, Boyd R.; Shelton, G. Diane; Lyons, Leslie A. // PLoS ONE;Oct2014, Vol. 9 Issue 10, p1 

    Myotonia congenita (MC) is a skeletal muscle channelopathy characterized by inability of the muscle to relax following voluntary contraction. Worldwide population prevalence in humans is 1∶100,000. Studies in mice, dogs, humans and goats confirmed myotonia associated with functional defects...

  • Novel CLCN1 mutations in Taiwanese patients with myotonia congenita. Jou, Shuo-Bin; Chang, Ling-I; Pan, Huichin; Chen, Pei-Ru; Hsiao, Kuang-Ming // Journal of Neurology;Jun2004, Vol. 251 Issue 6, p666 

    We have performed genetic screening on the skeletal muscle chloride channel gene (CLCN1) in Taiwanese population. A total of four patients with myotonia congenita (MC) together with 106 normal individuals were examined. All 23 exons of the CLCN1 gene were analysed by direct sequencing of PCR...

  • CLCN1 Mutations in Czech Patients with Myotonia Congenita, In Silico Analysis of Novel and Known Mutations in the Human Dimeric Skeletal Muscle Chloride Channel. Skálová, Daniela; Zídková, Jana; Voháňka, Stanislav; Mazanec, Radim; Mušová, Zuzana; Vondráček, Petr; Mrázová, Lenka; Kraus, Josef; Réblová, Kamila; Fajkusová, Lenka // PLoS ONE;Dec2013, Vol. 8 Issue 12, p1 

    Myotonia congenita (MC) is a genetic disease caused by mutations in the skeletal muscle chloride channel gene (CLCN1) encoding the skeletal muscle chloride channel (ClC-1). Mutations of CLCN1 result in either autosomal dominant MC (Thomsen disease) or autosomal recessive MC (Becker disease). The...

  • Impaired surface membrane insertion of homo- and heterodimeric human muscle chloride channels carrying amino-terminal myotonia-causing mutations. Ronstedt, Katharina; Sternberg, Damien; Detro-Dassen, Silvia; Gramkow, Thomas; Begemann, Birgit; Becher, Toni; Kilian, Petra; Grieschat, Matthias; Machtens, Jan-Philipp; Schmalzing, Günther; Fischer, Martin; Fahlke, Christoph // Scientific Reports;10/30/2015, p15382 

    Mutations in the muscle chloride channel gene (CLCN1) cause myotonia congenita, an inherited condition characterized by muscle stiffness upon sudden forceful movement. We here studied the functional consequences of four disease-causing mutations that predict amino acid substitutions Q43R, S70L,...

  • Becker's variant of myotonia congenita in two siblings- A clinico-genetic study. Bhattacharyya, Kalyan B.; Sengupta, P.; Basu, S.; Bhattacharya, N.P. // Neurology India;Sep2004, Vol. 52 Issue 3, p363 

    We report a family of a brother and sister of myotonia congenita, conforming to autosomal recessive transmission (Becker's variety). To the best of our knowledge, no account of a family of autosomal recessive myotonia (Becker's disease), has earlier been reported from India.

  • In vitro analysis of splice site mutations in the CLCN1 gene using the minigene assay. Ulzi, Gianna; Sansone, Valeria; Magri, Francesca; Corti, Stefania; Bresolin, Nereo; Comi, Giacomo; Lucchiari, Sabrina // Molecular Biology Reports;May2014, Vol. 41 Issue 5, p2865 

    Mutations in the chloride channel gene CLCN1 cause the allelic disorders Thomsen (dominant) and Becker (recessive) myotonia congenita (MC). The encoded protein, ClC-1, is the primary channel that mediates chloride (Cl) conductance in skeletal muscle. Mutations in CLCN1 lower the channel's...

  • A large cohort of myotonia congenita probands: novel mutations and a high-frequency mutation region in exons 4 and 5 of the CLCN1 gene. Brugnoni, Raffaella; Kapetis, Dimos; Imbrici, Paola; Pessia, Mauro; Canioni, Eleonora; Colleoni, Lara; de Rosbo, Nicole Kerlero; Morandi, Lucia; Cudia, Paola; Gashemi, Nasrin; Bernasconi, Pia; Desaphy, Jean-Francois; Conte, Diana; Mantegazza, Renato // Journal of Human Genetics;Sep2013, Vol. 58 Issue 9, p581 

    Myotonia congenita is a genetic disease characterized by impaired muscle relaxation after forceful contraction (myotonia) and caused by mutations in the chloride channel voltage-sensitive 1 (CLCN1) gene, encoding the voltage-gated chloride channel of skeletal muscle (ClC-1). In a large cohort of...

  • Novel chloride channel gene mutations in two unrelated Chinese families with myotonia congenita. Feng Gao; Fu Chan Ma; Zhe Feng Yuan; Cui Wei Yang; Hai Feng Li; Zhe Zhi Xia; Quan Xiang Shui; Ke Wen Jiang // Neurology India;Oct2010, Vol. 58 Issue 5, p743 

    Myotonia congenita (MC) is a genetic disease characterized by mutations in the muscle chloride channel gene (CLCN1). To date, approximately 130 different mutations on the CLCN1 gene have been identified. However, most of the studies have focused on Caucasians, and reports on CLCN1 mutations in...

Share

Read the Article

Courtesy of VIRGINIA BEACH PUBLIC LIBRARY AND SYSTEM

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics