Abstract
Myotonia congenita (MC) is a rare disorder characterized by stiffness and weakness of the limb and trunk muscles. Mutations in the SCN4A gene encoding the alpha-subunit of the voltage-gated sodium channel Nav1.4 have been reported to be responsible for sodium channel myotonia (SCM). The Nav1.4 channel is expressed in skeletal muscles, and its related channelopathies affect skeletal muscle excitability, which can manifest as SCM, paramyotonia and periodic paralysis. In this study, the missense mutation p.V445M was identified in two individual families with MC. To determine the functional consequences of having a mutated Nav1.4 channel, whole-cell patch-clamp recording of transfected Chinese hamster ovary cells was performed. Evaluation of the transient Na+ current found that a hyperpolarizing shift occurs at both the activation and inactivation curves with an increase of the window currents in the mutant channels. The Nav1.4 channel’s co-expression with the Navβ4 peptide can generate resurgent Na+ currents at repolarization following a depolarization. The magnitude of the resurgent currents is higher in the mutant than in the wild-type (WT) channel. Although the decay kinetics are comparable between the mutant and WT channels, the time to the peak of resurgent Na+ currents in the mutant channel is significantly protracted compared with that in the WT channel. These findings suggest that the p.V445M mutation in the Nav1.4 channel results in an increase of both sustained and resurgent Na+ currents, which may contribute to hyperexcitability with repetitive firing and is likely to facilitate recurrent myotonia in SCM patients.
Highlights
The human SCN4A gene encodes the alpha-subunit of the voltage-gated sodium channel Nav1.4, which is the pore-forming subunit
PP caused by Nav1.4 channelopathy can be divided into hypokalemic PP and hyperkalemic PP, which are associated with the blood potassium level
The candidate gene screening for a CLCN1 mutation did not find any sequence variant; further sequencing of SCN4A gene identified a missense variant, c.1333G>A, that results in the p.V445M change in both index cases
Summary
The human SCN4A gene encodes the alpha-subunit of the voltage-gated sodium channel Nav1.4, which is the pore-forming subunit. According to clinical and electromyographical (EMG) features, there are at least two disease entities for NDM: sodium channel myotonia (SCM) and paramyotonia congenita (PMC). The clinical features of dominant SCM are not significantly cold-sensitive and do not significantly decrease the compound motor action potential in an EMG test. Patients with SCM may sometimes present with exercise-induced, delayed-onset myotonia or acetazolamide-responsive myotonia [5]. Overlap, borderline or mixed clinical features between NDM and PP can be identified in patients with a Nav1.4 mutation [6,7,8,9]. More than seventy mutations in the SCN4A gene have been identified as pathogenic, and twelve are likely pathogenic [10]. The variable genotypes and phenotypes render it difficult to identify a correlation among Nav1.4 channelopathies
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