Substitutions of the S4DIV R2 residue (R1451) in Na1.4 lead to complex forms of paramyotonia congenita and periodic paralyses.

TitleSubstitutions of the S4DIV R2 residue (R1451) in Na1.4 lead to complex forms of paramyotonia congenita and periodic paralyses.
Publication TypeJournal Article
Year of Publication2018
AuteursPoulin, H, Gosselin-Badaroudine, P, Vicart, S, Habbout, K, Sternberg, D, Giuliano, S, Fontaine, B, Bendahhou, S, Nicole, S, Chahine, M
JournalSci Rep
Date Published2018 Feb 01

Mutations in Na1.4, 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.

Alternate JournalSci Rep
PubMed ID29391559
PubMed Central IDPMC5794747