Sodium Channel Myotonia Due to Novel Mutations in Domain I of Nav1.4.

Serena Pagliarani,Valeria A Sansone,Giovanni Meola,Marina Scarlato,Mauro Lo Monaco,Francesca Magri,Anna Modoni,Marzia Lecchi,Stefano C Previtali,Sabrina Lucchiari,Giacomo P Comi,Barbara Fossati,Elisa Redaelli

doi:10.3389/fneur.2020.00255

Abstract

Sodium channel myotonia is a form of muscle channelopathy due to mutations that affect the Nav1.4 channel. We describe seven families with a series of symptoms ranging from asymptomatic to clearly myotonic signs that have in common two novel mutations, p.Ile215Thr and p.Gly241Val, in the first domain of the Nav1.4 channel. The families described have been clinically and genetically evaluated. p.Ile215Thr and p.Gly241Val lie, respectively, on extracellular and intracellular loops of the first domain of the Nav1.4 channel. We assessed that the p.Ile215Thr mutation can be related to a founder effect in people from Southern Italy. Electrophysiological evaluation of the channel function showed that the voltage dependence of the activation for both the mutant channels was significantly shifted toward hyperpolarized potentials (Ile215Thr: −28.6 ± 1.5 mV and Gly241Val: −30.2 ± 1.3 mV vs. WT: −18.5 ± 1.3 mV). The slow inactivation was also significantly affected, whereas fast inactivation showed a different behavior in the two mutants. We characterized two novel mutations of the SCN4A gene expanding the knowledge about genetics of mild forms of myotonia, and we present, to our knowledge, the first homozygous patient with sodium channel myotonia.

Highlights

Myotonia is an impaired muscle relaxation after a voluntary muscle contraction and is the main feature of a group of heterogeneous skeletal muscle channelopathies named non-dystrophic myotonias (NDMs)
Over 70 mutations inherited in autosomal dominant fashion have been reported in the SCN4A gene and related to sodium channel myotonia (SCM) and periodic paralyzes. Some of these mutations are found in the first domain of the sodium channel and have been described to cause both SCM and paramyotonia congenita [7,8,9,10,11]
Statistical evaluation was performed using one-way analysis of variance (ANOVA) with statistical significance set at p < 0.05

Summary

INTRODUCTION

Myotonia is an impaired muscle relaxation after a voluntary muscle contraction and is the main feature of a group of heterogeneous skeletal muscle channelopathies named non-dystrophic myotonias (NDMs). The cell membrane enters a “refractory period” when it becomes inexcitable thanks to a double mechanism of Nav1.4 inactivation, either related to a fast or a slow kinetic Depending on their nature and localization, mutations in the SCN4A gene may enhance or decrease muscle excitability, and elicit different physiological reactions by the mutated channel which are related to different muscle diseases. Over 70 mutations inherited in autosomal dominant fashion have been reported in the SCN4A gene and related to SCM and periodic paralyzes Some of these mutations are found in the first domain of the sodium channel and have been described to cause both SCM and paramyotonia congenita [7,8,9,10,11]. Data from electrophysiological assays positively correlated with pathogenicity for both variants

MATERIALS AND METHODS

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DISCUSSION

ETHICS STATEMENT