Molecular Genetics of Skeletal Muscle Channelopathies

Abstract

Abstract The skeletal muscle channelopathies are disorders of muscle excitability due to disruption of the normal functioning of skeletal muscle ion channels. Such disruption to excitability can manifest clinically as episodic muscle weakness or myotonia resulting in a number of disorders classified as periodic paralysis and nondystrophic myotonias. Significant overlap is observed between these disorders in terms of both symptoms and causative genes. More than 200 mutations have been identified overall within the skeletal muscle voltage‐gated ion channel genes, with the main causative genes including CLCN‐1 , SCN4A and CACNA1S . However, ∼20% of patients have no genetic diagnosis despite a strong phenotype. Genetic research and functional analysis of mutations together have advanced our understanding of molecular disease mechanism as well as providing new insights into normal ion channel function. Key Concepts: Voltage‐gated ion channels are transmembrane proteins which selectively conduct ions across the plasma membrane on activation through a change in the membrane potential. Skeletal muscle channelopathies are caused by mutations located in functionally important areas of voltage‐gated ion channels. Symptoms manifest as intermittent alterations of skeletal muscle function. A number of different ion channels are known to cause the same disorders resulting in genetic heterogeneity. Mutations in the ion channels result in disruption of the sarcolemma membrane potential, which can cause myotonia through increased excitability or periodic paralysis due to decrease excitability. Symptoms of myotonia can be the result of mutations in either CLCN‐1 or SCN4A , whereas periodic paralysis is caused by mutations in CACNA1S , SCN4A , KCNJ2 or KCNJ18 . Phenotypic variability is seen even amongst patients within a single family. Significant symptom overlap occurs between disorders, which can lead to diagnostic confusion.