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Gene Review

CLCN1  -  chloride channel, voltage-sensitive 1

Homo sapiens

Synonyms: CLC1, Chloride channel protein 1, Chloride channel protein, skeletal muscle, ClC-1
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The CLCN1 gene encodes the votage gated skeletal muscle chloride channel, ClC-1. Mutations in CLCN1 cause Myotonia Congenita.


Disease relevance of CLCN1


High impact information on CLCN1


Chemical compound and disease context of CLCN1



Biological context of CLCN1


Anatomical context of CLCN1



Associations of CLCN1 with chemical compounds

  • The functional consequences of the novel CLCN1 sequence variants were explored by recording chloride currents from human embryonic kidney cells transiently expressing homo- or heterodimeric mutant channels [15].
  • This glycine residue is conserved in all known members of this class of chloride channel proteins [16].
  • An unusual restriction site in the CLC-1 locus in two GM families identified a mutation associated with that disease, a phenylalanine-to-cysteine substitution in putative transmembrane domain D8 [17].
  • Voltage-dependent blocks by intracellular and extracellular iodide help to distinguish two distinct ion binding sites within the hClC-1 conduction pathway [1].
  • These findings suggest that Gly 230 is critical for normal ion conductance in hClC-1 and that this residue resides within the channel pore [1].

Physical interactions of CLCN1




Regulatory relationships of CLCN1


Other interactions of CLCN1

  • An expansion in the ZNF9 gene causes PROMM in a previously described family with an incidental CLCN1 mutation [25].
  • The family was not sufficiently informative to exclude linkage to the sodium channel gene SCN4A or the chloride channel gene CLC1 [26].
  • The GM locus was again completely linked to both the CLCN1 and the TCRB gene in all families with a combined lod score of Z = 9.26 at a recombination fraction of theta = 0.00 [27].
  • These findings suggest that RPE 28 SV4 cells possess regulated chloride channels including CFTR and members of the ClC chloride channel family [28] .



Analytical, diagnostic and therapeutic context of CLCN1

  • The diagnosis of Myotonia Congenita is confirmed by identifying one or more causative mutations in the CLCN1 gene. However, not all sequence variants in CLCN1 are pathogenic. Classification of a CLCN1 sequence variants as pathogenic or benign is not always straightforward. Guidelines for the classification of sequence variants (in any gene) have been issued by the Clinical Molecular Genetics Society ( 
  • A large proportion of CLCN1 mutations are point mutations, and the effect of these on the function of the ClC-1 protein can be studied by voltage clamp. Sequence variants that impair ClC-1 function are likely to be pathogenic.
  • The authors used a mammalian cell (human embryonic kidney 293) expression system and the whole-cell voltage-clamp technique to functionally express and physiologically characterize five CLCN1 mutations [29].
  • All 23 exons of the CLCN1 gene were analysed by direct sequencing of PCR products to detect the nucleotide changes [30].
  • By means of two microelectrode voltage clamp recordings, we found that S(-)-CPP shifted the activation curve of the ClC-1 currents toward more positive potentials and decreased the residual conductance at negative membrane potential; both effects probably account for the decrease of gCl at resting potential of native muscle fibers [31].
  • Skeletal muscle CLC-1 mRNA levels were decreased by denervation [32].
  • Real-time quantitative RT-PCR did not reveal any obvious association between the total CLCN1 mRNA level in muscle and the mode of inheritance, but the dominant family with the most severe phenotype expressed twice the expected amount of the R894X mRNA allele [33].

Links to sites describing CLCN1 and Myotonia Congenita

  • NCBI gene review:  
  • Leiden Open Variation Database CLCN1 page:  
  • cDNA reference sequence for CLCN1:    


  1. A mutation in autosomal dominant myotonia congenita affects pore properties of the muscle chloride channel. Fahlke, C., Beck, C.L., George, A.L. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  2. Myotonia levior is a chloride channel disorder. Lehmann-Horn, F., Mailänder, V., Heine, R., George, A.L. Hum. Mol. Genet. (1995) [Pubmed]
  3. Proximal myotonic dystrophy--a family with autosomal dominant muscular dystrophy, cataracts, hearing loss and hypogonadism: heterogeneity of proximal myotonic syndromes? Udd, B., Krahe, R., Wallgren-Pettersson, C., Falck, B., Kalimo, H. Neuromuscul. Disord. (1997) [Pubmed]
  4. Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Charlet-B, N., Savkur, R.S., Singh, G., Philips, A.V., Grice, E.A., Cooper, T.A. Mol. Cell (2002) [Pubmed]
  5. The skeletal muscle sodium and chloride channel diseases. Hudson, A.J., Ebers, G.C., Bulman, D.E. Brain (1995) [Pubmed]
  6. Inhibition of skeletal muscle ClC-1 chloride channels by low intracellular pH and ATP. Bennetts, B., Parker, M.W., Cromer, B.A. J. Biol. Chem. (2007) [Pubmed]
  7. Multimeric structure of ClC-1 chloride channel revealed by mutations in dominant myotonia congenita (Thomsen). Steinmeyer, K., Lorenz, C., Pusch, M., Koch, M.C., Jentsch, T.J. EMBO J. (1994) [Pubmed]
  8. An aspartic acid residue important for voltage-dependent gating of human muscle chloride channels. Fahlke, C., Rüdel, R., Mitrovic, N., Zhou, M., George, A.L. Neuron (1995) [Pubmed]
  9. Spectrum of mutations in the major human skeletal muscle chloride channel gene (CLCN1) leading to myotonia. Meyer-Kleine, C., Steinmeyer, K., Ricker, K., Jentsch, T.J., Koch, M.C. Am. J. Hum. Genet. (1995) [Pubmed]
  10. Novel muscle chloride channel mutations and their effects on heterozygous carriers. Mailänder, V., Heine, R., Deymeer, F., Lehmann-Horn, F. Am. J. Hum. Genet. (1996) [Pubmed]
  11. Genomic organization of the human muscle chloride channel CIC-1 and analysis of novel mutations leading to Becker-type myotonia. Lorenz, C., Meyer-Kleine, C., Steinmeyer, K., Koch, M.C., Jentsch, T.J. Hum. Mol. Genet. (1994) [Pubmed]
  12. Chloride channels and hepatocellular function: prospects for molecular identification. Li, X., Weinman, S.A. Annu. Rev. Physiol. (2002) [Pubmed]
  13. Expression of CLCN voltage-gated chloride channel genes in human blood vessels. Lamb, F.S., Clayton, G.H., Liu, B.X., Smith, R.L., Barna, T.J., Schutte, B.C. J. Mol. Cell. Cardiol. (1999) [Pubmed]
  14. Differential expression of the human chloride channel genes in the trabecular meshwork under stress conditions. Comes, N., Gasull, X., Gual, A., Borrás, T. Exp. Eye Res. (2005) [Pubmed]
  15. Novel CLCN1 mutations with unique clinical and electrophysiological consequences. Wu, F.F., Ryan, A., Devaney, J., Warnstedt, M., Korade-Mirnics, Z., Poser, B., Escriva, M.J., Pegoraro, E., Yee, A.S., Felice, K.J., Giuliani, M.J., Mayer, R.F., Mongini, T., Palmucci, L., Marino, M., Rüdel, R., Hoffman, E.P., Fahlke, C. Brain (2002) [Pubmed]
  16. Molecular basis of Thomsen's disease (autosomal dominant myotonia congenita). George, A.L., Crackower, M.A., Abdalla, J.A., Hudson, A.J., Ebers, G.C. Nat. Genet. (1993) [Pubmed]
  17. The skeletal muscle chloride channel in dominant and recessive human myotonia. Koch, M.C., Steinmeyer, K., Lorenz, C., Ricker, K., Wolf, F., Otto, M., Zoll, B., Lehmann-Horn, F., Grzeschik, K.H., Jentsch, T.J. Science (1992) [Pubmed]
  18. Conservation of chloride channel structure revealed by an inhibitor binding site in ClC-1. Estévez, R., Schroeder, B.C., Accardi, A., Jentsch, T.J., Pusch, M. Neuron (2003) [Pubmed]
  19. Separation of drug transport and chloride channel functions of the human multidrug resistance P-glycoprotein. Gill, D.R., Hyde, S.C., Higgins, C.F., Valverde, M.A., Mintenig, G.M., Sepúlveda, F.V. Cell (1992) [Pubmed]
  20. A common sequence variation of the CLCNKB gene strongly activates ClC-Kb chloride channel activity. Jeck, N., Waldegger, P., Doroszewicz, J., Seyberth, H., Waldegger, S. Kidney Int. (2004) [Pubmed]
  21. Human ClC-3 is not the swelling-activated chloride channel involved in cell volume regulation. Weylandt, K.H., Valverde, M.A., Nobles, M., Raguz, S., Amey, J.S., Diaz, M., Nastrucci, C., Higgins, C.F., Sardini, A. J. Biol. Chem. (2001) [Pubmed]
  22. A short CIC-2 mRNA transcript is produced by exon skipping. Chu, S., Murray, C.B., Liu, M.M., Zeitlin, P.L. Nucleic Acids Res. (1996) [Pubmed]
  23. A short segment of the R domain of cystic fibrosis transmembrane conductance regulator contains channel stimulatory and inhibitory activities that are separable by sequence modification. Xie, J., Adams, L.M., Zhao, J., Gerken, T.A., Davis, P.B., Ma, J. J. Biol. Chem. (2002) [Pubmed]
  24. Increased expression of interleukin-9, interleukin-9 receptor, and the calcium-activated chloride channel hCLCA1 in the upper airways of patients with cystic fibrosis. Hauber, H.P., Manoukian, J.J., Nguyen, L.H., Sobol, S.E., Levitt, R.C., Holroyd, K.J., McElvaney, N.G., Griffin, S., Hamid, Q. Laryngoscope (2003) [Pubmed]
  25. An expansion in the ZNF9 gene causes PROMM in a previously described family with an incidental CLCN1 mutation. Lamont, P.J., Jacob, R.L., Mastaglia, F.L., Laing, N.G. J. Neurol. Neurosurg. Psychiatr. (2004) [Pubmed]
  26. PROMM: the expanding phenotype. A family with proximal myopathy, myotonia and deafness. Phillips, M.F., Rogers, M.T., Barnetson, R., Braun, C., Harley, H.G., Myring, J., Stevens, D., Wiles, C.M., Harper, P.S. Neuromuscul. Disord. (1998) [Pubmed]
  27. Evidence for genetic homogeneity in autosomal recessive generalised myotonia (Becker). Koch, M.C., Ricker, K., Otto, M., Wolf, F., Zoll, B., Lorenz, C., Steinmeyer, K., Jentsch, T.J. J. Med. Genet. (1993) [Pubmed]
  28. Chloride channel expression in cultured human fetal RPE cells: response to oxidative stress. Wills, N.K., Weng, T., Mo, L., Hellmich, H.L., Yu, A., Wang, T., Buchheit, S., Godley, B.F. Invest. Ophthalmol. Vis. Sci. (2000) [Pubmed]
  29. Functional consequences of chloride channel gene (CLCN1) mutations causing myotonia congenita. Zhang, J., Bendahhou, S., Sanguinetti, M.C., Ptácek, L.J. Neurology (2000) [Pubmed]
  30. Novel CLCN1 mutations in Taiwanese patients with myotonia congenita. Jou, S.B., Chang, L.I., Pan, H., Chen, P.R., Hsiao, K.M. J. Neurol. (2004) [Pubmed]
  31. Pharmacological characterization of chloride channels belonging to the ClC family by the use of chiral clofibric acid derivatives. Pusch, M., Liantonio, A., Bertorello, L., Accardi, A., De Luca, A., Pierno, S., Tortorella, V., Camerino, D.C. Mol. Pharmacol. (2000) [Pubmed]
  32. Altered gene expression in steroid-treated denervated muscle. Rich, M.M., Kraner, S.D., Barchi, R.L. Neurobiol. Dis. (1999) [Pubmed]
  33. Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype. Dunø, M., Colding-Jørgensen, E., Grunnet, M., Jespersen, T., Vissing, J., Schwartz, M. Eur. J. Hum. Genet. (2004) [Pubmed]
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