Nature 354, 304 - 308 (28 November 1991); doi:10.1038/354304a0

Inactivation of muscle chloride channel by transposon insertion in myotonic mice

Klaus Steinmeyer^*, Rainer Klocke^†, Christoph Ortland^*, Monika Gronemeier^†, Harald Jockusch^†, Stefan GrÜnder^* & Thomas J. Jentsch^*‡

^*Centre for Molecular Neurobiology (ZMNH), Hamburg University, Martinistrasse 52, D-2000 Hamburg 20, Germany
^†Developmental Biology Unit, W7, Bielefeld University, PO Box 8640, D-4800 Bielefeld 1, Germany
^‡To whom corresspondence should be addressed.

MYOTONIA (stiffness and impaired relaxation of skeletal muscle) is a symptom of several diseases caused by repetitive firing of action potentials in muscle membranes¹. Purely myotonic human diseases are dominant myotonia congenita (Thomsen) and recessive generalized myotonia (Becker), whereas myotonic dystrophy is a systemic disease. Muscle hyperexcitability was attributed to defects in sodium channels^2,3 and/or to a decrease in chloride conductance (in Becker's myotonia⁴ and in genetic animal models^5–10). Experimental blockage of Cl^- conductance (normally 70–85% of resting conductance in muscle11) in fact elicits myotonia^1,9. ADR (ref. 12) mice are a realistic animal model^{5–7,12–18} for recessive autosomal myotonia. In addition to Cl^- conductance⁵, many other parameters^6,12,16 are changed in muscles of homozygous animals. We have now cloned the major mammalian skeletal muscle chloride channel (C1C-1)¹⁹. Here wereport that in ADR mice a transposon of the ETn family^20–23 has inserted into the corresponding gene, destroying its coding potential for several membrane-spanning domains. Together with the lack of recombination between the Clc-1 gene and the adr locus, this strongly suggests a lack of functional chloride channels as the primary cause of mouse myotonia.

References

1.	Rüdel, R. & Lehmann-Horn, F. Physiol. Rev. 65, 310−356 (1985). | PubMed | ISI | ChemPort |
2.	Iaizzo, P. A. et al. Neuromusc. Disord. 1, 47−53 (1991). | PubMed | ChemPort |
3.	Franke, C. et al. Muscle Nerve 14, 762−770 (1991). | Article | PubMed | ISI | ChemPort |
4.	Rüdel, R., Ricker, K. & Lehmann-Horn, F. Muscle Nerve 11, 202−211 (1988). | PubMed |
5.	Mehrke, G., Brinkmeier, H., & Jockusch, H. Muscle Nerve 11, 440−446 (1988). | Article | PubMed | ISI | ChemPort |
6.	Jockusch, H. in The Dynamic State of Muscle Fibers (ed. Pette, D.) 429−443 (Walter de Gruyter, New York, 1990).
7.	Rüdel, R. Trends Neurosci. 13, 1−3 (1990). | PubMed |
8.	Lipicky, R. J. & Bryant, S. H. J. gen. Physiol. 50, 89−111 (1966). | Article | PubMed | ChemPort |
9.	Bryant, S. H. & Morales-Aguilera, A. J. Physiol., Lond. 219, 367−383 (1971). | PubMed | ISI | ChemPort |
10.	Adrian, R. H. & Bryant, S. H. J. Physiol., Lond. 240, 505−515 (1974). | ChemPort |
11.	Bretag, A. H. Physiol. Rev. 67, 618−724 (1987). | PubMed | ChemPort |
12.	Watkins, W. J. & Watt, D. C. Lab. Anim. 18, 1−6 (1984). | PubMed | ChemPort |
13.	Reininghaus, J., Füchtbauer, E.-M., Bertram, K. & Jockusch, H. Muscle Nerve 11, 433−439 (1988). | Article | PubMed | ChemPort |
14.	Füchtbauer, E.-M., Reininghaus, J. & Jocksuch, H. Proc. natn. Acad. Sci. U.S.A. 85, 3880−3884 (1988).
15.	Brinkmeier, H. & Jockusch, H. Biochem. biophys. Res. Commun. 148, 1383−1389 (1987). | Article | PubMed | ChemPort |
16.	Jockusch, H., Reininghaus, J., Stuhlfauth, I. & Zippel, M. Eur. J. Biochem. 171, 101−105 (1988). | Article | PubMed | ChemPort |
17.	Költgen, D., Brinkmeier, H. & Jockusch, H. Muscle Nerve 14, 775−780 (1991). | PubMed |
18.	Jockusch, H., Schenk, S. & Gronemeier, M. Mouse Genome 86, 216 (1990).
19.	Steinmeyer, K., Ortland, C. & Jentsch, T. J. Nature 354, 301−304 (1991). | Article | PubMed | ISI | ChemPort |
20.	Brûlet, P., Kaghad, M., Xu, Y.-S., Croissant, O. & Jacob, F. Proc. natn. Acad. Sci. U.S.A. 80, 5641−5645 (1983). | ChemPort |
21.	Brûlet, P., Condamine, H. & Jacob, F. Proc. natn. Acad. Sci. U.S.A. 82, 2054−2058 (1985).
22.	Sonigo, P. et al. Proc. natn. Acad. Sci. U.S.A. 84, 3768−3771 (1987). | ChemPort |
23.	Shell, B., Szurek, P. & Dunnick, W. Molec. cell. Biol. 7, 1364−1370 (1987). | PubMed | ChemPort |
24.	Heller, A. H., Eicher, E. M., Hallett, M. & Sidman, R. L. J. Neurosci. 2, 924−933 (1982). | PubMed | ChemPort |
25.	Neumann, P. & Weber, T. Mouse News Lett. 83, 157 (1989).
26.	Jentsch, T. J., Steinmeyer, K. & Schwarz, G. Nature 348, 510−514 (1990). | Article | PubMed | ISI | ChemPort |
27.	Conte Camerino, D., De Luca, A., Mambrini, M. & Vrbovà, G. Pflügers Arch. 413, 568−570 (1989). | Article | ChemPort |
28.	Lipicky, R. J., Bryant S. H. & Salmon, J. H. J. clin. Invest. 50, 2091−2103 (1971). | PubMed | ChemPort |
29.	Friedmann, J. M., Leibel, R. L. & Bahary, N. Mammalian Genome 1, 130−144 (1991). | PubMed |
30.	Meyers, J. C. et al. Proc. natn. Acad. Sci. U.S.A. 78, 3516−3520 (1981). | ChemPort |
31.	Dean, M. et al. Nature 318, 385−388 (1985). | Article | PubMed | ISI | ChemPort |
32.	Quinto, C. et al. Proc. natn. Acad. Sci. U.S.A. 79, 31−35 (1982). | ChemPort |
33.	Yanagi, Y. et al. Nature 308, 145−149 (1984). | Article | PubMed | ISI | ChemPort |
34.	Bucan, M. et al. EMBO J. 5, 2899−2905 (1986). | PubMed | ChemPort |
35.	Wilkie, T. M. & Palmiter, R. D. Molec cell. Biol. 7, 1646−1655 (1987). | PubMed | ChemPort |