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A novel dominant mutation of the Na_v1.4 -subunit domain I leading to sodium channel myotonia

From the Department of Pharmacology and Toxicology (S.P., H.A.), University of Lausanne, Switzerland; Institute for Research in Ophthalmology (L.T., D.S.), Sion, and University of Lausanne, Switzerland; Centre for Integrative Physiology (L.C.), Membrane Biology Group, School of Biomedical Sciences, University of Edinburgh, United Kingdom; Department of Neurology (L.K., K.M.R., J.-M.B.), University of Berne, Switzerland; Ecole polytechnique fédérale de Lausanne (D.S.), Switzerland; and Division of Neurology (J.-M.B.), Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Address correspondence and reprint requests to either Dr. Jean-Marc Burgunder, Neurology Office, Steinerstrasse 45, CH 3006 Bern, Switzerland; or Dr. Hugues Abriel, Department of Pharmacology and Toxicology, University of Lausanne, Switzerland jean-marc.burgunder{at}dkf.unibe.ch

Background: Mutations in SCN4A may lead to myotonia.

Methods: Presentation of a large family with myotonia, including molecular studies and patch clamp experiments using human embryonic kidney 293 cells expressing wild-type and mutated channels.

Results: In a large family with historic data on seven generations and a clear phenotype, including myotonia at movement onset, with worsening by cold temperature, pregnancy, mental stress, and especially after rest after intense physical activity, but without weakness, the phenotype was linked with the muscle sodium channel gene (SCN4A) locus, in which a novel p.I141V mutation was found. This modification is located within the first transmembrane segment of domain I of the Na_v1.4 subunit, a region where no mutation has been reported so far. Patch clamp experiments revealed a mutation-induced hyperpolarizing shift (–12.9 mV) of the voltage dependence of activation, leading to a significant increase (approximately twofold) of the window current amplitude. In addition, the mutation shifted the voltage dependence of slow inactivation by –8.7 mV and accelerated the entry to this state.

Conclusions: We propose that the gain-of-function alteration in activation leads to the observed myotonic phenotype, whereas the enhanced slow inactivation may prevent depolarization-induced paralysis.

Abbreviations: cDNA = complementary DNA; HEK = human embryonic kidney; I_Na = sodium current; IV = p.I141V; NA = not applicable; SSCP = single-stranded conformational polymorphism; TTX = tetrodotoxin; WT = wild type.

*These two authors provided similar contributions to the work presented in this article.

Supported by a grant from the Swiss National Science Foundation (PP00-110638/1 to H.A.).

Disclosure: The authors report no disclosures.

Received February 27, 2008. Accepted in final form August 8, 2008.

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