Karima Habbout1, Hugo Poulin1, François Rivier1, Serena Giuliano1, Damien Sternberg1, Bertrand Fontaine1, Bruno Eymard1, Raul Juntas Morales1, Bernard Echenne1, Louise King1, Michael G Hanna1, Roope Männikkö1, Mohamed Chahine1, Sophie Nicole1, Said Bendahhou2. 1. From UMR7370 CNRS (K.H., S.G., S.B.), LP2M, Labex ICST, University Nice Sophia-Antipolis, Faculté de Médecine, Nice, France; Centre de Recherche (H.P., M.C.), Institut Universitaire en Santé Mentale de Québec; Department of Medicine (H.P., M.C.), Université Laval, Québec City, Canada; CHRU Montpellier (F.R., R.J.M., B.E.), Neuropédiatrie & Centre de Référence Maladies Neuromusculaires, Montpellier; Université de Montpellier (F.R., B.E.); INSERM (F.R.), U1046, CNRS, UMR9214, Montpellier; INSERM (D.S., B.F., B.E., S.N.), U1127, Paris; Sorbonne Universités (D.S., B.F., B.E., S.N.), UPMC University Paris 6, UMR S1127; CNRS (D.S., B.F., B.E., S.N.), UMR 7225, Paris; Institut du Cerveau et de la Moelle Épinière (D.S., B.F., B.E., S.N.), ICM, Paris; AP-HP (D.S., B.F., B.E.), Centres de Référence des Canalopathies Musculaires et des Maladies Neuro-musculaires Paris-Est, Service de Biochimie Métabolique, Hôpital de la Pitié Salpêtrière, France; and MRC Centre for Neuromuscular Diseases (L.K., M.G.H., R.M.), UCL Institute of Neurology, London, UK. 2. From UMR7370 CNRS (K.H., S.G., S.B.), LP2M, Labex ICST, University Nice Sophia-Antipolis, Faculté de Médecine, Nice, France; Centre de Recherche (H.P., M.C.), Institut Universitaire en Santé Mentale de Québec; Department of Medicine (H.P., M.C.), Université Laval, Québec City, Canada; CHRU Montpellier (F.R., R.J.M., B.E.), Neuropédiatrie & Centre de Référence Maladies Neuromusculaires, Montpellier; Université de Montpellier (F.R., B.E.); INSERM (F.R.), U1046, CNRS, UMR9214, Montpellier; INSERM (D.S., B.F., B.E., S.N.), U1127, Paris; Sorbonne Universités (D.S., B.F., B.E., S.N.), UPMC University Paris 6, UMR S1127; CNRS (D.S., B.F., B.E., S.N.), UMR 7225, Paris; Institut du Cerveau et de la Moelle Épinière (D.S., B.F., B.E., S.N.), ICM, Paris; AP-HP (D.S., B.F., B.E.), Centres de Référence des Canalopathies Musculaires et des Maladies Neuro-musculaires Paris-Est, Service de Biochimie Métabolique, Hôpital de la Pitié Salpêtrière, France; and MRC Centre for Neuromuscular Diseases (L.K., M.G.H., R.M.), UCL Institute of Neurology, London, UK. said.bendahhou@unice.fr.
Abstract
OBJECTIVE: To determine the molecular basis of a complex phenotype of congenital muscle weakness observed in an isolated but consanguineous patient. METHODS: The proband was evaluated clinically and neurophysiologically over a period of 15 years. Genetic testing of candidate genes was performed. Functional characterization of the candidate mutation was done in mammalian cell background using whole cell patch clamp technique. RESULTS: The proband had fatigable muscle weakness characteristic of congenital myasthenic syndrome with acute and reversible attacks of most severe muscle weakness as observed in periodic paralysis. We identified a novel homozygous SCN4A mutation (p.R1454W) linked to this recessively inherited phenotype. The p.R1454W substitution induced an important enhancement of fast and slow inactivation, a slower recovery for these inactivated states, and a frequency-dependent regulation of Nav1.4 channels in the heterologous expression system. CONCLUSION: We identified a novel loss-of-function mutation of Nav1.4 that leads to a recessive phenotype combining clinical symptoms and signs of congenital myasthenic syndrome and periodic paralysis, probably by decreasing channel availability for muscle action potential genesis at the neuromuscular junction and propagation along the sarcolemma.
OBJECTIVE: To determine the molecular basis of a complex phenotype of congenital muscle weakness observed in an isolated but consanguineous patient. METHODS: The proband was evaluated clinically and neurophysiologically over a period of 15 years. Genetic testing of candidate genes was performed. Functional characterization of the candidate mutation was done in mammalian cell background using whole cell patch clamp technique. RESULTS: The proband had fatigable muscle weakness characteristic of congenital myasthenic syndrome with acute and reversible attacks of most severe muscle weakness as observed in periodic paralysis. We identified a novel homozygous SCN4A mutation (p.R1454W) linked to this recessively inherited phenotype. The p.R1454W substitution induced an important enhancement of fast and slow inactivation, a slower recovery for these inactivated states, and a frequency-dependent regulation of Nav1.4 channels in the heterologous expression system. CONCLUSION: We identified a novel loss-of-function mutation of Nav1.4 that leads to a recessive phenotype combining clinical symptoms and signs of congenital myasthenic syndrome and periodic paralysis, probably by decreasing channel availability for muscle action potential genesis at the neuromuscular junction and propagation along the sarcolemma.
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