Mutations in Nav1.4 and Nav1.5 α-subunits have been associated with muscular and cardiac channelopathies, respectively. Despite intense research on the structure and function of these channels, a lot of information is still missing to delineate the various physiological and pathophysiological processes underlying their activity at the molecular level. Nav1.4 and Nav1.5 sequences are similar, suggesting structural and functional homologies between the two orthologous channels. This also suggests that any characteristics described for one channel subunit may shed light on the properties of the counterpart channel subunit. In this review article, after a brief clinical description of the muscular and cardiac channelopathies related to Nav1.4 and Nav1.5 mutations, respectively, we compare the knowledge accumulated in different aspects of the expression and function of Nav1.4 and Nav1.5 α-subunits: the regulation of the two encoding genes (SCN4A and SCN5A), the associated/regulatory proteins and at last, the functional effect of the same missense mutations detected in Nav1.4 and Nav1.5. First, it appears that more is known on Nav1.5 expression and accessory proteins. Because of the high homologies of Nav1.5 binding sites and equivalent Nav1.4 sites, Nav1.5-related results may guide future investigations on Nav1.4. Second, the analysis of the same missense mutations in Nav1.4 and Nav1.5 revealed intriguing similarities regarding their effects on membrane excitability and alteration in channel biophysics. We believe that such comparison may bring new cues to the physiopathology of cardiac and muscular diseases.

/pdf/physiological-and-pathophysiological-insights-of-nav1-4-and-5579bm04m9.pdf

Physiological and Pathophysiological Insights of Nav1.4 and Nav1.5 Comparison

Heterozygous CLCN1 mutations can modulate phenotype in sodium channel myotonia.

Mutations in the skeletal muscle channel (SCN4A), encoding the Nav1.4 voltage-gated sodium channel, are causative of a variety of muscle channelopathies, including non-dystrophic myotonias and periodic paralysis. The effects of many of these mutations on channel function have been characterized both in vitro and in vivo. However, little is known about the consequences of SCN4A mutations downstream from their impact on the electrophysiology of the Nav1.4 channel. Here we report the discovery of a novel SCN4A mutation (c.1762A>G; p.I588V) in a patient with myotonia and periodic paralysis, located within the S1 segment of the second domain of the Nav1.4 channel. Using N-ethyl-N-nitrosourea mutagenesis, we generated and characterized a mouse model (named draggen), carrying the equivalent point mutation (c.1744A>G; p.I582V) to that found in the patient with periodic paralysis and myotonia. Draggen mice have myotonia and suffer from intermittent hind-limb immobility attacks. In-depth characterization of draggen mice uncovered novel systemic metabolic abnormalities in Scn4a mouse models and provided novel insights into disease mechanisms. We discovered metabolic alterations leading to lean mice, as well as abnormal AMP-activated protein kinase activation, which were associated with the immobility attacks and may provide a novel potential therapeutic target.

/pdf/novel-mutations-in-human-and-mouse-scn4a-implicate-ampk-in-dgbqm232ca.pdf

Novel mutations in human and mouse SCN4A implicate AMPK in myotonia and periodic paralysis

Voltage-gated sodium channels (Nav) are widely expressed as macro-molecular complexes in both excitable and non-excitable tissues. In excitable tissues, the upstroke of the action potential is the result of the passage of a large and rapid influx of sodium ions through these channels. NaV dysfunction has been associated with an increasingly wide range of neurological, muscular and cardiac disorders. The purpose of this review is to summarize the recently identified sodium channel mutations that are linked to hyper-excitability phenotypes and associated with the alteration of the activation process of voltage gated sodium channels. Indeed, several clinical manifestations that demonstrate an alteration of tissue excitability were recently shown to be strongly associated with the presence of mutations that affect the activation process of the Nav. These emerging genotype-phenotype correlations have expanded the clinical spectrum of sodium channelopathies to include disorders which feature a hyper-excitability phenotype that may or may not be associated with a cardiomyopathy. The p.I141V mutation in SCN4A and SCN5A, as well as its homologous p.I136V mutation in SCN9A, are interesting examples of mutations that have been linked to inherited hyperexcitability myotonia, exercise-induced polymorphic ventricular arrhythmias and erythromelalgia, respectively. Regardless of which sodium channel isoform is investigated, the substitution of the isoleucine to valine in the locus 141 induces similar modifications in the biophysical properties of the Nav by shifting the voltage-dependence of steady state activation toward more negative potentials.

/pdf/cellular-hyper-excitability-caused-by-mutations-that-alter-4nzyiffp0d.pdf

Cellular hyper-excitability caused by mutations that alter the activation process of voltage-gated sodium channels.

Voltage-gated sodium channels have been implicated in numerous inherited paroxysmal disorders of the nervous system, muscle, and heart. Our goal is to provide a framework that helps neurologists understand the clinical and treatment implications of sodium channel variants they encounter in clinical practice. This will be accomplished through our objectives of (1) recognizing the relationship between location of a missense sodium channel gene variant and its effect on channel function, and (2) categorizing clinical phenotype based on functional effect of a variant. The relationship between location, function, and treatment response is also discussed. These interactions can be illustrated by the sodium channelopathies seen in people with epilepsy but generalize beyond that disorder. Ann Neurol 2018;83:1-9.

/pdf/location-a-surrogate-for-personalized-treatment-of-sodium-zze8oh578u.pdf

Location: A surrogate for personalized treatment of sodium channelopathies.

A novel mutation in SCN4A causes severe myotonia and school-age-onset paralytic episodes.

https://www.pedneur.com/article/S0887-8994(15)00044-2/pdf

Phenotypic variability in childhood of skeletal muscle sodium channelopathies.

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A novel mutation in SCN4A causes severe myotonia and school-age-onset paralytic episodes.

Phenotypic variability in childhood of skeletal muscle sodium channelopathies.