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

Ting Ting Lee, Xiao Dong Zhang, Chao Chin Chuang, Jing Jer Chen, Yi An Chen, Shu Ching Chen, Tsung-Yu Chen, Chih Yung Tang

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere55930
JournalPLoS One
Volume8
Issue number2
DOIs
StatePublished - Feb 12 2013

Fingerprint

Myotonia Congenita
chloride channels
Chloride Channels
mutation
Degradation
mutants
Mutation
degradation
protein synthesis
protein transport
muscular diseases
Myotonia
pathophysiology
Proteins
Current density
Inheritance Patterns
inheritance (genetics)
Muscular Diseases
Protein Transport
Mutant Proteins

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Lee, T. T., Zhang, X. D., Chuang, C. C., Chen, J. J., Chen, Y. A., Chen, S. C., ... Tang, C. Y. (2013). Myotonia Congenita Mutation Enhances the Degradation of Human CLC-1 Chloride Channels. PLoS One, 8(2), [e55930]. https://doi.org/10.1371/journal.pone.0055930

Myotonia Congenita Mutation Enhances the Degradation of Human CLC-1 Chloride Channels. / Lee, Ting Ting; Zhang, Xiao Dong; Chuang, Chao Chin; Chen, Jing Jer; Chen, Yi An; Chen, Shu Ching; Chen, Tsung-Yu; Tang, Chih Yung.

In: PLoS One, Vol. 8, No. 2, e55930, 12.02.2013.

Research output: Contribution to journalArticle

Lee, TT, Zhang, XD, Chuang, CC, Chen, JJ, Chen, YA, Chen, SC, Chen, T-Y & Tang, CY 2013, 'Myotonia Congenita Mutation Enhances the Degradation of Human CLC-1 Chloride Channels', PLoS One, vol. 8, no. 2, e55930. https://doi.org/10.1371/journal.pone.0055930
Lee TT, Zhang XD, Chuang CC, Chen JJ, Chen YA, Chen SC et al. Myotonia Congenita Mutation Enhances the Degradation of Human CLC-1 Chloride Channels. PLoS One. 2013 Feb 12;8(2). e55930. https://doi.org/10.1371/journal.pone.0055930
Lee, Ting Ting ; Zhang, Xiao Dong ; Chuang, Chao Chin ; Chen, Jing Jer ; Chen, Yi An ; Chen, Shu Ching ; Chen, Tsung-Yu ; Tang, Chih Yung. / Myotonia Congenita Mutation Enhances the Degradation of Human CLC-1 Chloride Channels. In: PLoS One. 2013 ; Vol. 8, No. 2.
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