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This Article Full Text Full Text (PDF) All Versions of this Article: 554/3/635    most recent jphysiol.2003.053082v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bouhours, M. Articles by Tabti, N. Search for Related Content PubMed PubMed Citation Articles by Bouhours, M. Articles by Tabti, N.

¹ INSERM U546, Faculté de Médecine Pitié-Salpêtrière (UPMC) 75013 Paris, France ² Laboratoire de Neurophysiologie, Faculté de Médecine Pitié-Salpêtrière (UPMC) 75013 Paris, France ³ Fédération de Neurologie, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France ⁴ Laboratoire de Biochimie, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France ⁵ (Resocanaux) Service de Neurologie, CHU Bordeaux, 33604 France

Paramyotonia congenita (PC) is a dominantly inherited skeletal muscle disorder caused by missense mutations in the SCN4A gene encoding the pore-forming subunit (hSkM1) of the skeletal muscle Na⁺ channel. Muscle stiffness is the predominant clinical symptom. It is usually induced by exposure to cold and is aggravated by exercise. The most prevalent PC mutations occur at T1313 on DIII–DIV linker, and at R1448 on DIV–S4 of the subunit. Only one substitution has been described at T1313 (T1313M), whereas four distinct amino-acid substitutions were found at R1448 (R1448C/H/P/S). We report herein a novel mutation at position 1313 (T1313A) associated with a typical phenotype of PC. We stably expressed T1313A or wild-type (hSkM1) channels in HEK293 cells, and performed a detailed study on mutant channel gating defects using the whole-cell configuration of the patch-clamp technique. T1313A mutation impaired Na⁺ channel fast inactivation: it slowed and reduced the voltage sensitivity of the kinetics, accelerated the recovery, and decreased the voltage-dependence of the steady state. Slow inactivation was slightly enhanced by the T1313A mutation: the voltage dependence was shifted toward hyperpolarization and its steepness was reduced compared to wild-type. Deactivation from the open state assessed by the tail current decay was only slowed at positive potentials. This may be an indirect consequence of disrupted fast inactivation. Deactivation from the inactivation state was hastened. The T1313A mutation did not modify the temperature sensitivity of the Na⁺ channel per se. However, gating kinetics of the mutant channels were further slowed with cooling, and reached levels that may represent the threshold for myotonia. In conclusion, our results confirm the role of T1313 residue in Na⁺ channel fast inactivation, and unveil subtle changes in other gating processes that may influence the clinical phenotype.

(Received 8 August 2003; accepted after revision 10 November 2003; first published online 14 November 2003)
Corresponding author N. Tabti: INSERM U546, Laboratoire de Neurophysiologie, Faculté de Médecine Pitié-Salpêtrière, 91 Bd de l'Hôpital, 75013 Paris, France.  Email: nacira.tabti{at}chups.jussieu.fr

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