Functional expression of the Ile693Thr Na+ channel mutation associated with paramyotonia congenita in a human cell line

Authors

  • Emmanuelle Plassart-Schiess,

    1. INSERM CJF9608, Hôpital de la Salpêtrière, 47 boulevard de l'Hôpital, 75651 Paris cedex 13, France
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  • Loïc Lhuillier,

    1. Laboratoire de Physiologie Générale, UFR des Sciences, Université Paris XII, 94 000 Créteil, France
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  • Alfred L. George Jr,

    1. Department of Medicine and Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA
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  • Bertrand Fontaine,

    1. INSERM CJF9608, Hôpital de la Salpêtrière, 47 boulevard de l'Hôpital, 75651 Paris cedex 13, France
    2. Fédération de Neurologie, Hôpital de la Salpêtrière, Paris, France
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  • Nacira Tabti

    1. INSERM CJF9608, Hôpital de la Salpêtrière, 47 boulevard de l'Hôpital, 75651 Paris cedex 13, France
    2. Laboratoire de Physiologie Générale, UFR des Sciences, Université Paris XII, 94 000 Créteil, France
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Corresponding author N. Tabti: INSERM CJF9608, Hôpital de la Salpêtrière, 47 boulevard de l'Hôpital, 75651 Paris cedex 13, France. Email: tabti@univ-paris12.fr

Abstract

  • 1The Ile693Thr mutation of the skeletal muscle Na+ channel α-subunit is associated with an unusual phenotype of paramyotonia congenita characterized by cold-induced muscle weakness but no stiffness. This mutation occurs in the S4-S5 linker of domain II, a region that has not been previously implicated in paramyotonia congenita.
  • 2The Ile693Thr mutation was introduced into the human skeletal muscle Na+ gene for functional expression in human embryonic kidney (HEK) cells. The currents expressed were recorded with the whole-cell voltage-clamp technique.
  • 3In comparison with wild-type currents, Ile693Thr mutant currents showed a clear shift of about −9 mV in the voltage dependence of activation.
  • 4In contrast to other mutations of the Na+ channel known to cause paramyotonia congenita, the Ile693Thr mutation did not induce any significant change in the kinetics, nor in the voltage dependence, of fast inactivation.
  • 5In conclusion, this study provides further evidence of the involvement of the S4-S5 linker in the voltage dependence of Na+ channel activation. The negative shift in the voltage dependence found in this mutation must be associated to other defects, plausibly an impairment of the slow inactivation, to account for the long periods of muscle weakness experienced by the patients.

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