Myotonia congenita mutation enhances the degradation of human CLC-1 chloride channels.
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 inherita...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3570542?pdf=render |
| _version_ | 1811207230519771136 |
|---|---|
| author | Ting-Ting Lee Xiao-Dong Zhang Chao-Chin Chuang Jing-Jer Chen Yi-An Chen Shu-Ching Chen Tsung-Yu Chen Chih-Yung Tang |
| author_facet | Ting-Ting Lee Xiao-Dong Zhang Chao-Chin Chuang Jing-Jer Chen Yi-An Chen Shu-Ching Chen Tsung-Yu Chen Chih-Yung Tang |
| author_sort | Ting-Ting Lee |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T03:59:29Z |
| format | Article |
| id | doaj.art-8db1fce855d14a9489fc0d29c9e73a2f |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T03:59:29Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-8db1fce855d14a9489fc0d29c9e73a2f2022-12-22T03:48:44ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0182e5593010.1371/journal.pone.0055930Myotonia congenita mutation enhances the degradation of human CLC-1 chloride channels.Ting-Ting LeeXiao-Dong ZhangChao-Chin ChuangJing-Jer ChenYi-An ChenShu-Ching ChenTsung-Yu ChenChih-Yung TangMyotonia 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.http://europepmc.org/articles/PMC3570542?pdf=render |
| spellingShingle | Ting-Ting Lee Xiao-Dong Zhang Chao-Chin Chuang Jing-Jer Chen Yi-An Chen Shu-Ching Chen Tsung-Yu Chen Chih-Yung Tang Myotonia congenita mutation enhances the degradation of human CLC-1 chloride channels. PLoS ONE |
| title | Myotonia congenita mutation enhances the degradation of human CLC-1 chloride channels. |
| title_full | Myotonia congenita mutation enhances the degradation of human CLC-1 chloride channels. |
| title_fullStr | Myotonia congenita mutation enhances the degradation of human CLC-1 chloride channels. |
| title_full_unstemmed | Myotonia congenita mutation enhances the degradation of human CLC-1 chloride channels. |
| title_short | Myotonia congenita mutation enhances the degradation of human CLC-1 chloride channels. |
| title_sort | myotonia congenita mutation enhances the degradation of human clc 1 chloride channels |
| url | http://europepmc.org/articles/PMC3570542?pdf=render |
| work_keys_str_mv | AT tingtinglee myotoniacongenitamutationenhancesthedegradationofhumanclc1chloridechannels AT xiaodongzhang myotoniacongenitamutationenhancesthedegradationofhumanclc1chloridechannels AT chaochinchuang myotoniacongenitamutationenhancesthedegradationofhumanclc1chloridechannels AT jingjerchen myotoniacongenitamutationenhancesthedegradationofhumanclc1chloridechannels AT yianchen myotoniacongenitamutationenhancesthedegradationofhumanclc1chloridechannels AT shuchingchen myotoniacongenitamutationenhancesthedegradationofhumanclc1chloridechannels AT tsungyuchen myotoniacongenitamutationenhancesthedegradationofhumanclc1chloridechannels AT chihyungtang myotoniacongenitamutationenhancesthedegradationofhumanclc1chloridechannels |