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Electrophysiological Characteristics of Six Mutations in hClC-1 of Korean Patients with Myotonia Congenita

  • Ha, Kotdaji (Department of Physiology, Seoul National University, College of Medicine) ;
  • Kim, Sung-Young (Department of Physiology, Seoul National University, College of Medicine) ;
  • Hong, Chansik (Department of Physiology, Seoul National University, College of Medicine) ;
  • Myeong, Jongyun (Department of Physiology, Seoul National University, College of Medicine) ;
  • Shin, Jin-Hong (Department of Neurology, Research Institute for Convergence of Biomedical Research and Technology, Pusan University Yangsan Hospital) ;
  • Kim, Dae-Seong (Department of Neurology, Research Institute for Convergence of Biomedical Research and Technology, Pusan University Yangsan Hospital) ;
  • Jeon, Ju-Hong (Department of Physiology, Seoul National University, College of Medicine) ;
  • So, Insuk (Department of Physiology, Seoul National University, College of Medicine)
  • Received : 2013.09.23
  • Accepted : 2014.01.28
  • Published : 2014.03.31

Abstract

ClC-1 is a member of a large family of voltage-gated chloride channels, abundantly expressed in human skeletal muscle. Mutations in ClC-1 are associated with myotonia congenita (MC) and result in loss of regulation of membrane excitability in skeletal muscle. We studied the electrophysiological characteristics of six mutants found among Korean MC patients, using patch clamp methods in HEK293 cells. Here, we found that the autosomal dominant mutants S189C and P480S displayed reduced chloride conductances compared to WT. Autosomal recessive mutant M128I did not show a typical rapid deactivation of Cl- currents. While sporadic mutant G523D displayed sustained activation of $Cl^-$ currents in the whole cell traces, the other sporadic mutants, M373L and M609K, demonstrated rapid deactivations. $V_{1/2}$ of these mutants was shifted to more depolarizing potentials. In order to identify potential effects on gating processes, slow and fast gating was analyzed for each mutant. We show that slow gating of the mutants tends to be shifted toward more positive potentials in comparison to WT. Collectively, these six mutants found among Korean patients demonstrated modifications of channel gating behaviors and reduced chloride conductances that likely contribute to the physiologic changes of MC.

References

  1. Accardi, A., and Pusch, M. (2000). Fast and slow gating relaxations in the muscle chloride channel CLC-1. J. Gen. Physiol. 116, 433-444. https://doi.org/10.1085/jgp.116.3.433
  2. Aromataris, E.C., Rychkov, G.Y., Bennetts, B., Hughes, B.P., Bretag, A.H., and Roberts, M.L. (2001). Fast and slow gating of CLC-1: differential effects of 2-(4-chlorophenoxy) propionic acid and dominant negative mutations. Mol. Pharmacol. 60, 200-208. https://doi.org/10.1124/mol.60.1.200
  3. Bryant, S.H., and Morales-Aguilera, A. (1971). Chloride conductance in normal and myotonic muscle fibres and the action of monocarboxylic aromatic acids. J. Physiol. 219, 367-383. https://doi.org/10.1113/jphysiol.1971.sp009667
  4. Colding-Jorgensen, E. (2002). Phenotypic variability in myotonia congenita. Muscle Nerve 32, 19-34.
  5. Dulhunty, A.F. (1979). Distribution of potassium and chloride permeability over the surface and T-tubule membranes of mammalian skeletal muscle. J. Membr. Biol. 45, 293-310. https://doi.org/10.1007/BF01869290
  6. Fahlke, C., Rosenbohm, A., Mitrovic, N., George, A.L Jr., and Rudel, R. (1996). Mechanism of voltage-dependent gating in skeletal muscle chloride channels. Biophys. J. 71, 695-706. https://doi.org/10.1016/S0006-3495(96)79269-X
  7. Dutka, T.L., Murphy, R.M., Stephenson, D.G., and Lamb, G.D. (2000). Chloride conductance in the transverse tubular system of rat skeletal muscle fibres: importance inexcitation-contraction coupling and fatigue. J. Physiol. 586, 875-887.
  8. Dutzler, R. (2006). The clc family of chloride channels and transporters. Curr. Opin. Struct. Biol. 4, 439-446.
  9. Dutzler, R., Campbell, E.B., Cadene, M., Chait, B.T., and MacKinnon, R. (2002). X-ray structure of a ClC chloride channel at 3.0 A reveals the molecular basis of anion selectivity. Nature 415, 287-294. https://doi.org/10.1038/415287a
  10. Fahlke, C., Beck, C.L., and George, A.L. Jr. (1997a). A mutation in autosomal dominant myotonia congenita affects pore properties of the muscle chloride channel. Proc. Natl. Acad. Sci. USA 94, 2729-2734. https://doi.org/10.1073/pnas.94.6.2729
  11. Fahlke, C., Knittle, T., Gurnett, C.A., Campbell, K.P., and George, A.L Jr. (1997b). Subunit stoichiometry of human muscle chloride channels. J. Gen. Physiol. 109, 93-104. https://doi.org/10.1085/jgp.109.1.93
  12. Fahlke, C., Desai, R.R., Gillani, N., and George, A.L. Jr. (2001). Residues lining the inner pore vestibule of human muscle chloride channels. J. Biol. Chem. 276, 1759-1765. https://doi.org/10.1074/jbc.M007649200
  13. Fialho, D., Schorge, S., and Pucovska., U., Davies, N.P., Labrum, R., Haworth, A., Stanley, E., Sud, R., Wakeling, W., Davis, M.B., et al. (2007). Chloride channel myotonia: exon 8 hot-spot for dominant-negative interactions. Brain 130, 3265-3274. https://doi.org/10.1093/brain/awm248
  14. George, A.L Jr., Crackower, M.A., Abdalla, J.A., Hudson, A.J., and Ebers, G.C. (1993). Molecular basis of Thomsen's disease (autosomal dominant myotonia congenita). Nat. Genet. 3, 305-310. https://doi.org/10.1038/ng0493-305
  15. Jentsch, T.J., Lorenz, C., Pusch, M., and Steinmeyer, K. (2010). Myotonias due to CLC-1 chloride channel mutations. Soc. Gen. Physiol. 50, 149-159.
  16. Grunnet, M., Jespersen, T., Colding-Jorgensen, E., Schwartz, M., Klaerke, D.A., Vissing, J., Olesen, S.P., and Duno, M. (2003). Characterization of two new dominant ClC-1 channel mutations associated with myotonia. Muscle Nerve. 28, 722-732. https://doi.org/10.1002/mus.10501
  17. Heiny, J.A., Valle, J.R., and Bryant, S.H. (1990). Optical evidence for a chloride conductance in the T-system of frog skeletal muscle. Pflugers Arch. 416, 288-295. https://doi.org/10.1007/BF00392065
  18. Hsiao, K.M., Huang, R.Y., Tang, P.H., and Lin, M.J. (2010). Functional study of CLC-1 mutants expressed in Xenopus oocytes reveals that a C-terminal region Thr891-Ser892-Thr893 is responsible for the effects of protein kinase C activator. Cell. Physiol. Biochem. 25, 687-694. https://doi.org/10.1159/000315088
  19. Koch, M.C., Steinmeyer, K., Lorenz, C., Ricker, K., Wolf, F., Otto, M., Zoll, B., Lehmann-Horn, F., Grzeschik, K.H., and Jentsch, T.J. (1992). The skeletal muscle chloride channel in dominant and recessive human myotonia. Science 257, 797-800. https://doi.org/10.1126/science.1379744
  20. Koch, M.C., Ricker, K., Otto, M., Wolf, F., Zoll, B., Lorenz, C., Steinmeyer, K., and Jentsch, T.J. (1993). Evidence for genetic homogeneity in autosomal recessive generalised myotonia (Becker). J. Med. Genet. 30, 914-917. https://doi.org/10.1136/jmg.30.11.914
  21. Lossin, C., and George, A.L Jr. (2008). Myotonia congenita. Adv. Genet. 63, 25-55. https://doi.org/10.1016/S0065-2660(08)01002-X
  22. Mailander, V., Heine, R., Deymeer, F., and Lehmann-Horn, F. (1996). Novel muscle chloride channel mutations and their effects on heterozygous carriers. Am. J. Hum. Genet. 58, 317-324.
  23. Markovic, S., and Dutzler, R. (2007). The structure of the cytoplasmic domain of the chloride channel ClC-Ka reveals a conserved interaction interface. Structure 15, 715-725. https://doi.org/10.1016/j.str.2007.04.013
  24. Meyer, S., and Dutzler, R. (2006). Crystal structure of the cytoplasmic domain of the chloride channel ClC-0. Structure 14, 299-307. https://doi.org/10.1016/j.str.2005.10.008
  25. Moon, I.S., Kim, H.S., Shin, J.H., Park, Y.E., Park, K.H., Shin, Y.B., Bae, J.S., Choi, Y.C., and Kim, D.S. (2009). Novel CLCN1 mutations and clinical features of Korean patients with myotonia congenita. J. Korean Med. Sci. 24, 1038-44. https://doi.org/10.3346/jkms.2009.24.6.1038
  26. Matulef, K., Howery, A.E., Kobertz, W.R., Bois, J.D., and Maduke, M. (2008). Discovery of potent CLC chloride channel inhibitors. ACS Chem. Biol. 3, 419-428. https://doi.org/10.1021/cb800083a
  27. Richman, D.P., Yu, Y., Lee, T.T., Tseng, P.Y., Yu, W.P., Maselli, R.A., Tang, C.Y., and Chen, T.Y. (2012). Dominantly inherited myotonia congenita resulting from a mutation that increases open probability of the muscle chloride channel, CLC-1 Neuromol. Med. 14, 328-337. https://doi.org/10.1007/s12017-012-8190-1
  28. Tang, C.Y., and Chen, T.Y. (2011). Physiology and pathophysiology of CLC-1: mechanisms of a chloride channel disease, myotonia. J. Biomed. Biotechnol. 2011, 685328.
  29. 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., et al. (2002). Novel CLCN1 mutations with unique clinical and electrophysiological consequences. Brain 125, 2392-2407. https://doi.org/10.1093/brain/awf246

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