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Gene Review

Clcn1  -  chloride channel 1

Mus musculus

Synonyms: Chloride channel protein 1, Chloride channel protein, skeletal muscle, ClC-1, Clc-1, Clc1, ...
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Disease relevance of Clcn1

  • Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy [1].
  • Exploring the mammalian neuromuscular system by analysis of mutations: spinal muscular atrophy and myotonia [2].
  • Thus it appears that, at the level of the muscle fibre, myotonia and muscular dystrophy attenuate each other [3].
  • The detection of the stop codon in the adrmto allele is further indication of the identity of the Clc-1 chloride channel with the adr myotonia gene in the mouse, because a chain termination close to the N terminus would necessarily destroy gene function [4].
  • Also, myofibers infected with a recombinant Semliki Forest virus (SFV) expressing myc-tagged ClC-1 showed intracellular localization of the protein [5].

Psychiatry related information on Clcn1


High impact information on Clcn1


Chemical compound and disease context of Clcn1


Biological context of Clcn1

  • Nevertheless, in +/adr heterozygous, phenotypically wild type (WT) animals, the expression levels of both alleles correspond to the gene dosage [17].
  • The results indicate that peak ClC-1 current density at -140 mV is reduced >70% (-48.5 +/- 3.6 and -14.0 +/- 1.6 pA/pF, respectively) and the kinetics of channel deactivation increased in FDB fibers obtained from 18-20- d-old HSA(LR) mice [18].
  • Thus, the structural gene for PV, designated Pva, maps to chromosome 15 of the mouse whereas the adr mutation shows no linkage with markers on this chromosome [19].
  • MYOTONIA (stiffness and impaired relaxation of skeletal muscle) is a symptom of several diseases caused by repetitive firing of action potentials in muscle membranes [20].
  • This conductance is essential for membrane-potential stability, as its block by 9-anthracene-carboxylic acid and other drugs causes myotonia [21].

Anatomical context of Clcn1

  • Here, we show that overexpression of Mbnl1 in vivo mediated by transduction of skeletal muscle with a recombinant adeno-associated viral vector rescues disease-associated muscle hyperexcitability, or myotonia, in the HSA(LR) poly(CUG) mouse model for DM [1].
  • In the mouse, there is very little ClC-1 mRNA in myotubes, and its concentration increases steeply during postnatal development, suggesting a role of the motor nerve in ClC-1 expression [17].
  • Neither effect of denervation was observed in myotonic mice (homozygous for the alleles adr or adrK), suggesting that spontaneous electrical activity of the hyperexcitable sarcolemma may substitute for nerve activity [17].
  • Furthermore, electrical myotonia was demonstrated in isolated ADR muscle fibers devoid of nerve endings [22].
  • Mutants homozygous for du, mto, spa and tg had virtually normal lipid levels in both the optic and peripheral nerves [23].

Associations of Clcn1 with chemical compounds

  • The gene mutation in the mouse, 'arrested development of righting response', adr, causes a defect of chloride conductance of the muscle fibre membrane leading to the symptoms of myotonia [Mehrke, G., Brinkmeier, H. and Jockusch, H. (1988) Muscle & Nerve 11, 440-446] [24].
  • In order to study the nature of two other alleles, adrmto and adrK, we have analyzed overlapping Clc-1 cDNA amplification products by the hydroxylamine and osmium tetroxide modification technique and direct sequencing [4].
  • Glycolytic, pentose-phosphate shunt and transaminase enzymes in gastrocnemius muscle, liver, heart, and brain of two mouse mutants, 129 J-dy and A2g-adr, with abnormal muscle function [25].
  • Alanine and aspartate aminotransferase activities were normal or low in 129 J-dy muscle but increased to approximately 200% in A2G-adr muscle [25].
  • The pentose-phosphate shunt enzymes, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, were both greatly increased in the gastrocnemius of 129 J-dy mice, but only the former was slightly increased in A2G-adr muscle [25].

Physical interactions of Clcn1

  • To further study the putative gamma-butyrolactone site of the GABAA/chloride channel complex, constrained derivatives of convulsant and anticonvulsant alpha,alpha-disubstituted gamma-butyrolactones (alpha-spirocyclopropyl- and alpha-spirocyclopentyl-gamma-butyrolactones) were synthesized and evaluated biologically [26].

Regulatory relationships of Clcn1


Other interactions of Clcn1


Analytical, diagnostic and therapeutic context of Clcn1

  • No changes in GSL expression were found in the A2G-adr mouse, while muscle of the BL6-wr mouse showed increased intensity of immunofluorescence in stainings with anti-lactosylceramide and anti-GM3(Neu5Ac) antibodies [32].
  • Muscle hyperexcitability was attributed to defects in sodium channels and/or to a decrease in chloride conductance (in Becker's myotonia and in genetic animal models) [20].
  • The B6MT mouse showed moderate to severe action myotonia, and electromyography revealed myotonic discharge [33].
  • Similar myotonic symptoms could be evoked in muscle fibres from 7 day wildtype mice after substitution of the external chloride with impermeant anions or by activators of protein kinase C. The genotypes of 3-day-old mice cannot be inferred from inspection and, thus, were identified by Southern blotting with a ClC-1 probe [34].
  • The mouse Clc1/myotonia gene: ETn insertion, a variable AATC repeat, and PCR diagnosis of alleles [35].


  1. Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy. Kanadia, R.N., Shin, J., Yuan, Y., Beattie, S.G., Wheeler, T.M., Thornton, C.A., Swanson, M.S. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  2. Exploring the mammalian neuromuscular system by analysis of mutations: spinal muscular atrophy and myotonia. Jockusch, H., Kaupmann, K., Gronemeier, M., Schleef, M., Klocke, R. Prog. Neurobiol. (1994) [Pubmed]
  3. Mutual interference of myotonia and muscular dystrophy in the mouse: a study on ADR-MDX double mutants. Heimann, P., Augustin, M., Wieneke, S., Heising, S., Jockusch, H. Neuromuscul. Disord. (1998) [Pubmed]
  4. Nonsense and missense mutations in the muscular chloride channel gene Clc-1 of myotonic mice. Gronemeier, M., Condie, A., Prosser, J., Steinmeyer, K., Jentsch, T.J., Jockusch, H. J. Biol. Chem. (1994) [Pubmed]
  5. Regulated sarcolemmal localization of the muscle-specific ClC-1 chloride channel. Papponen, H., Kaisto, T., Myllylä, V.V., Myllylä, R., Metsikkö, K. Exp. Neurol. (2005) [Pubmed]
  6. Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts. Sarkar, P.S., Appukuttan, B., Han, J., Ito, Y., Ai, C., Tsai, W., Chai, Y., Stout, J.T., Reddy, S. Nat. Genet. (2000) [Pubmed]
  7. Developmental shift in bidirectional functions of taurine-sensitive chloride channels during cortical circuit formation in postnatal mouse brain. Yoshida, M., Fukuda, S., Tozuka, Y., Miyamoto, Y., Hisatsune, T. J. Neurobiol. (2004) [Pubmed]
  8. Molecular structure and physiological function of chloride channels. Jentsch, T.J., Stein, V., Weinreich, F., Zdebik, A.A. Physiol. Rev. (2002) [Pubmed]
  9. Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy. Mahadevan, M.S., Yadava, R.S., Yu, Q., Balijepalli, S., Frenzel-McCardell, C.D., Bourne, T.D., Phillips, L.H. Nat. Genet. (2006) [Pubmed]
  10. Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz-Jampel syndrome (chondrodystrophic myotonia). Nicole, S., Davoine, C.S., Topaloglu, H., Cattolico, L., Barral, D., Beighton, P., Hamida, C.B., Hammouda, H., Cruaud, C., White, P.S., Samson, D., Urtizberea, J.A., Lehmann-Horn, F., Weissenbach, J., Hentati, F., Fontaine, B. Nat. Genet. (2000) [Pubmed]
  11. Overt nephrogenic diabetes insipidus in mice lacking the CLC-K1 chloride channel. Matsumura, Y., Uchida, S., Kondo, Y., Miyazaki, H., Ko, S.B., Hayama, A., Morimoto, T., Liu, W., Arisawa, M., Sasaki, S., Marumo, F. Nat. Genet. (1999) [Pubmed]
  12. Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mankodi, A., Takahashi, M.P., Jiang, H., Beck, C.L., Bowers, W.J., Moxley, R.T., Cannon, S.C., Thornton, C.A. Mol. Cell (2002) [Pubmed]
  13. The breast cancer beta 4 integrin and endothelial human CLCA2 mediate lung metastasis. Abdel-Ghany, M., Cheng, H.C., Elble, R.C., Pauli, B.U. J. Biol. Chem. (2001) [Pubmed]
  14. Niflumic acid suppresses interleukin-13-induced asthma phenotypes. Nakano, T., Inoue, H., Fukuyama, S., Matsumoto, K., Matsumura, M., Tsuda, M., Matsumoto, T., Aizawa, H., Nakanishi, Y. Am. J. Respir. Crit. Care Med. (2006) [Pubmed]
  15. The loss of the chloride channel, ClC-5, delays apical iodide efflux and induces a euthyroid goiter in the mouse thyroid gland. van den Hove, M.F., Croizet-Berger, K., Jouret, F., Guggino, S.E., Guggino, W.B., Devuyst, O., Courtoy, P.J. Endocrinology (2006) [Pubmed]
  16. The multidrug resistance of tumour cells was reversed by tetrandrine in vitro and in xenografts derived from human breast adenocarcinoma MCF-7/adr cells. Fu, L.W., Zhang, Y.M., Liang, Y.J., Yang, X.P., Pan, Q.C. Eur. J. Cancer (2002) [Pubmed]
  17. Role of innervation, excitability, and myogenic factors in the expression of the muscular chloride channel ClC-1. A study on normal and myotonic muscle. Klocke, R., Steinmeyer, K., Jentsch, T.J., Jockusch, H. J. Biol. Chem. (1994) [Pubmed]
  18. Muscle chloride channel dysfunction in two mouse models of myotonic dystrophy. Lueck, J.D., Mankodi, A., Swanson, M.S., Thornton, C.A., Dirksen, R.T. J. Gen. Physiol. (2007) [Pubmed]
  19. cDNA sequence and chromosomal localization of the mouse parvalbumin gene, Pva. Zühlke, C., Schöffl, F., Jockusch, H., Simon, D., Guénet, J.L. Genet. Res. (1989) [Pubmed]
  20. Inactivation of muscle chloride channel by transposon insertion in myotonic mice. Steinmeyer, K., Klocke, R., Ortland, C., Gronemeier, M., Jockusch, H., Gründer, S., Jentsch, T.J. Nature (1991) [Pubmed]
  21. Primary structure and functional expression of a developmentally regulated skeletal muscle chloride channel. Steinmeyer, K., Ortland, C., Jentsch, T.J. Nature (1991) [Pubmed]
  22. Myotonia and neuromuscular transmission in the mouse. Költgen, D., Brinkmeier, H., Jockusch, H. Muscle Nerve (1991) [Pubmed]
  23. A survey of neurological mutant mice. II. Lipid composition of myelinated tissue in possible myelin mutants. Ganser, A.L., Kerner, A.L., Brown, B.J., Davisson, M.T., Kirschner, D.A. Dev. Neurosci. (1988) [Pubmed]
  24. Opposite regulation of the mRNAs for parvalbumin and p19/6.8 in myotonic mouse muscle. Kluxen, F.W., Schöffl, F., Berchtold, M.W., Jockusch, H. Eur. J. Biochem. (1988) [Pubmed]
  25. Glycolytic, pentose-phosphate shunt and transaminase enzymes in gastrocnemius muscle, liver, heart, and brain of two mouse mutants, 129 J-dy and A2g-adr, with abnormal muscle function. Soothill, P.W., Kouseibati, F., Watts, R.L., Watts, D.C. J. Neurochem. (1981) [Pubmed]
  26. Alpha-spirocyclopentyl- and alpha-spirocyclopropyl-gamma-butyrolactones: conformationally constrained derivatives of anticonvulsant and convulsant alpha,alpha-disubstituted gamma-butyrolactones. Peterson, E.M., Xu, K., Holland, K.D., McKeon, A.C., Rothman, S.M., Ferrendelli, J.A., Covey, D.F. J. Med. Chem. (1994) [Pubmed]
  27. Regulation of the ClC-2 lung epithelial chloride channel by glycosylation of SP1. Vij, N., Zeitlin, P.L. Am. J. Respir. Cell Mol. Biol. (2006) [Pubmed]
  28. Inactivation of the murine cftr gene abolishes cAMP-mediated but not Ca(2+)-mediated secretagogue-induced volume decrease in small-intestinal crypts. Valverde, M.A., O'Brien, J.A., Sepúlveda, F.V., Ratcliff, R., Evans, M.J., Colledge, W.H. Pflugers Arch. (1993) [Pubmed]
  29. On the mechanism by which dopamine inhibits prolactin release in the anterior pituitary. Pokras, R., Tabakoff, B. Life Sci. (1982) [Pubmed]
  30. Haploinsuffciency for znf9 in znf9(+/-) mice is associated with multiorgan abnormalities resembling myotonic dystrophy. Chen, W., Wang, Y., Abe, Y., Cheney, L., Udd, B., Li, Y.P. J. Mol. Biol. (2007) [Pubmed]
  31. Myotonic ADR-MDX mutant mice show less severe muscular dystrophy than MDX mice. Krämer, R., Lochmüller, H., Abicht, A., Rüdel, R., Brinkmeier, H. Neuromuscul. Disord. (1998) [Pubmed]
  32. Immunohistological analyses of neutral glycosphingolipids and gangliosides in normal mouse skeletal muscle and in mice with neuromuscular diseases. Cacic, M., Sostarić, K., Weber-Schürholz, S., Müthing, J. Glycoconj. J. (1995) [Pubmed]
  33. A novel murine myotonia congenita without molecular defects in the ClC-1 and the SCN4A. Shirakawa, T., Sakai, K., Kitagawa, Y., Hori, A., Hirose, G. Neurology (2002) [Pubmed]
  34. Development of electrical myotonia in the ADR mouse: role of chloride conductance in myotubes and neonatal animals. Wischmeyer, E., Nolte, E., Klocke, R., Jockusch, H., Brinkmeier, H. Neuromuscul. Disord. (1993) [Pubmed]
  35. The mouse Clc1/myotonia gene: ETn insertion, a variable AATC repeat, and PCR diagnosis of alleles. Schnülle, V., Antropova, O., Gronemeier, M., Wedemeyer, N., Jockusch, H., Bartsch, J.W. Mamm. Genome (1997) [Pubmed]
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