Sodium channel mutations in paramyotonia congenita and hyperkalemic periodic paralysis

TLDR

Periodic paralyses such as hyperkalemic periodic paralysis and paramyotonia congenita arise from allelic defects in the skeletal muscle sodium channel alpha‑subunit, as shown by clinical, electrophysiological, and genetic studies across multiple families. The study reports a novel L1433R mutation causing paramyotonia congenita and aims to characterize its phenotypic effects to elucidate sodium channel structure‑function relationships. The authors identified a leucine‑to‑arginine substitution in the S3 segment of domain 4 of the sodium channel (L1433R) that produces the paramyotonia congenita phenotype.

Abstract

Clinical and electrophysiological data have outlined a spectrum of similar yet distinct periodic paralyses, including potassium-sensitive (hyperkalemic periodic paralysis [HYPP]) and temperature-sensitive (paramyotonia congenita [PC]) forms. Recent work has revealed that these disorders result from allelic defects in the alpha-subunit of the adult, human skeletal muscle sodium channel. We report an additional mutation, a leucine-->arginine substitution in the S3 segment of domain 4 (L1433R), that results in the PC phenotype. Five other HYPP and PC families have been ascertained, and previously reported sodium channel mutations have been identified in each. Characterization of these mutations and phenotypic variations in such families will contribute to the understanding of sodium channel structure and function relationships, as well as channel malfunction in the periodic paralyses.