Abstract
Mutations in NaV1.4, the skeletal muscle voltage-gated Na+ channel, underlie several skeletal muscle channelopathies. We report here the functional characterization of two substitutions targeting the R1451 residue and resulting in 3 distinct clinical phenotypes. The R1451L is a novel pathogenic substitution found in two unrelated individuals. The first individual was diagnosed with non-dystrophic myotonia, whereas the second suffered from an unusual phenotype combining hyperkalemic and hypokalemic episodes of periodic paralysis (PP). The R1451C substitution was found in one individual with a single attack of hypoPP induced by glucocorticoids. To elucidate the biophysical mechanism underlying the phenotypes, we used the patch-clamp technique to study tsA201 cells expressing WT or R1451C/L channels. Our results showed that both substitutions shifted the inactivation to hyperpolarized potentials, slowed the kinetics of inactivation, slowed the recovery from slow inactivation and reduced the current density. Cooling further enhanced these abnormalities. Homology modeling revealed a disruption of hydrogen bonds in the voltage sensor domain caused by R1451C/L. We concluded that the altered biophysical properties of R1451C/L well account for the PMC-hyperPP cluster and that additional factors likely play a critical role in the inter-individual differences of clinical expression resulting from R1451C/L.
Highlights
Voltage-gated Na+ channels (VGSC) are responsible for the initial rise and propagation of action potentials (APs) in excitable cells
This 27-year-old man, without familial history, had a single episode of hypokalemic quadriplegia following a glucocorticoid injection done one day after a high carbohydrate meal. He did not report cold-induced stiffness or weakness at the time of examination. He was found to be heterozygous for the c.4351c > t mutation resulting in the p.Arg1451Cys amino acid substitution
The present study investigated the biophysical properties of two distinct substitutions in NaV1.4 of the same amino acid residue (R1451C and R1451L), found in individuals with three different and unusual clinical phenotypes
Summary
Voltage-gated Na+ channels (VGSC) are responsible for the initial rise and propagation of action potentials (APs) in excitable cells. Over 50 SCN4A mutations[1] have been associated with six skeletal muscle Na+ channelopathies forming a clinical spectrum ranging from severe forms of Na+ channel myotonia (SCM, hyperexcitability) to fetal hypokinesia (hypoexcitability)[2,3]. Among these extreme phenotypes are found the paramyotonia congenita (PMC), periodic paralysis (PP), and congenital myasthenic syndromes (CMS)[2]. All dominantly-inherited hypoPP phenotypes are due to amino-acid substitution of arginine residues in the segment 4 (S4) of DI-III VSDs that cause a dominant-negative effect with a gating pore current responsible for a proton or sodium leak and paradoxical depolarization of the skeletal muscle membrane. Our results showed that both substitutions shifted steady-state inactivation to hyperpolarized potentials, reduced the current density, impaired the recovery from slow inactivation and increase the overall inactivation rate
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