Molecular genetics of skeletal muscle channelopathies

Abstract

Kubota T., Takahashi M.P.. Molecular genetics of skeletal muscle channelopathies. Journal of Human Genetics (2025); https://doi.org/10.1038/s10038-025-01370-w.Skeletal muscle channelopathies are genetic disorders associated with variants in genes encoding ion channels and related proteins expressed in skeletal muscle. Most commonly, these involve genes encoding voltage-gated ion channels (VGICs) that regulate sarcolemmal excitability, including CLCN1 for ClC-1, SCN4A for the Nav1.4 α subunit, CACNA1S for the Cav1.1 α subunit, and KCNJ2 for Kir2.1. Skeletal muscle channelopathies primarily manifest with two clinical symptoms: myotonia, characterized by delayed muscle relaxation, and paralysis and classified into two disease types: non-dystrophic myotonia and periodic paralysis. Recent advances in the clinical application of next-generation sequencing have improved diagnostic rate and provided epidemiological evidence of the diseases. Furthermore, atypical phenotypes have been identified, indicating that skeletal muscle channelopathies present a broad clinical spectrum. This review provides an updated overview of the clinical and genetic aspects of skeletal muscle channelopathies and discusses key issues that require further investigation