https://scholars.lib.ntu.edu.tw/handle/123456789/506991
標題: | Dominantly inherited myotonia congenita resulting from a mutation that increases open probability of the muscle chloride channel CLC-1 | 作者: | Richman D.P. Yu Y. Lee T.T. Tseng P.-Y. Yu W.-P. Maselli R.A. CHIH-YUNG TANG Chen T.Y. |
關鍵字: | Chloride channel; CLCN1; Dominant; Gain of function; Muscle; Myotonia congenita | 公開日期: | 2012 | 卷: | 14 | 期: | 4 | 起(迄)頁: | 328-337 | 來源出版物: | NeuroMolecular Medicine | 摘要: | Myotonia congenita-inducing mutations in the muscle chloride channel CLC-1 normally result in reduced open probability (Po) of this channel. One well-accepted mechanism of the dominant inheritance of this disease involves a dominant-negative effect of the mutation on the function of the common-gate of this homodimeric, doublebarreled molecule. We report here a family with myotonia congenita characterized by muscle stiffness and clinical and electrophysiologic myotonic phenomena transmitted in an autosomal dominant pattern. DNA sequencing of DMPK and ZNF9 genes for myotonic muscular dystrophy types I and II was normal, whereas sequencing of CLC-1 encoding gene, CLCN1, identified a single heterozygous missense mutation, G233S. Patch-clamp analyses of this mutant CLC-1 channel in Xenopus oocytes revealed an increased Po of the channel's fast-gate, from ?0.4 in the wild type to>0.9 in the mutant at -90 mV. In contrast, the mutant exhibits a minimal effect on the Po of the commongate. These results are consistent with the structural prediction that the mutation site is adjacent to the fast-gate of the channel. Overall, the mutant could lead to a significantly reduced dynamic response of CLC-1 to membrane depolarization, from a fivefold increase in chloride conductance in the wild type to a twofold increase in the mutant-this might result in slower membrane repolarization during an action potential. Since expression levels of the mutant and wild-type subunits in artificial model cell systems were unable to explain the disease symptoms, the mechanism leading to dominant inheritance in this family remains to be determined. ? Springer Science+Business Media, LLC 2012. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84870478532&doi=10.1007%2fs12017-012-8190-1&partnerID=40&md5=25d00d0b8d86bb5f4678669fbd768753 https://scholars.lib.ntu.edu.tw/handle/123456789/506991 |
ISSN: | 1535-1084 | DOI: | 10.1007/s12017-012-8190-1 | SDG/關鍵字: | chloride channel; chloride channel CLC 1; myotonic dystrophy protein kinase; unclassified drug; animal cell; article; autosomal dominant inheritance; channel gating; CLCN1 gene; controlled study; dmpk gene; DNA sequence; electrophysiology; gene; gene sequence; genetic disorder; heterozygote; human; human cell; human tissue; missense mutation; molecular pathology; muscle action potential; muscle atonia; muscle rigidity; muscular dystrophy; muscular dystrophy type 1; muscular dystrophy type 2; mutant; mutational analysis; nonhuman; nucleotide sequence; oocyte; prediction; priority journal; probability; Xenopus; ZNF9 gene; Adult; Animals; Child; Chloride Channels; Chlorides; Disease Progression; Female; Genes, Dominant; HEK293 Cells; Humans; Ion Channel Gating; Male; Models, Molecular; Muscle Cramp; Mutation, Missense; Myotonia Congenita; Oocytes; Pedigree; Point Mutation; Protein Conformation; Recombinant Fusion Proteins; Transfection; Xenopus laevis |
顯示於: | 生理學科所 |
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