Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy

Abstract

Skeletal muscle ion channelopathies (SMICs) are a large heterogeneous group of rare genetic disorders caused by mutations in genes encoding ion channel subunits in the skeletal muscle mainly characterized by myotonia or periodic paralysis, potentially resulting in long-term disabilities. However, with the development of new molecular technologies, new genes and new phenotypes, including progressive myopathies, have been recently discovered, markedly increasing the complexity in the field. In this regard, new advances in SMICs show a less conventional role of ion channels in muscle cell division, proliferation, differentiation, and survival. Hence, SMICs represent an expanding and exciting field. Here, we review current knowledge of SMICs, with a description of their clinical phenotypes, cellular and molecular pathomechanisms, and available treatments.

Keywords: CACNA1S; CLCN1; KCNJ2; SCN4A; ion channels; myopathies; myotonia; periodic paralysis.

Figure 1

A schematic representation of skeletal muscle sodium channelopathies, reporting the mode of inheritance (AD: autosomal dominant; AR: autosomal recessive), disease name, mutation effects on sodium channel function, and main symptoms.

Figure 2

A schematic representation of the calcium ion-permeable channels involved in skeletal muscle myopathies. The TRPV4 channel is highly expressed even in motor neurons, and mutations cause a number of peripheral neuropathies with implications for skeletal muscles. The contribution of muscular TRPV4 channels to these diseases is unknown. The Cav3.2 channel is expressed mainly in embryonic cells, which contributes to myoblast differentiation and fusion during muscle development. (CRAC: Calcium-release activated calcium; DHPR: Dihydropyridine receptor; GoF: gain of function; HMSN2C: Hereditary motor and sensory neuropathy type 2C; HypoPP1: Hypokalemic periodic paralysis type 1; LoF: loss of function; MHS: Malignant hyperthermia susceptibility; NAM: Native American myopathy; NEM3: Nemaline myopathy type 3; SMA: Spinal muscular atrophy; SPSMA: Scapuloperoneal spinal muscular atrophy; SR: sarcoplasmic reticulum; STRMK: Stormorken syndrome; TAM: Tubular aggregate myopathy).

Figure 3

A schematic representation of the potassium channels involved in skeletal muscle myopathies. Potassium channel subunits are represented in lateral view embedded in the membrane, while multimeric assemblies are represented from the top view. The inward-rectifier K⁺ channels are heterotetrameric assemblies of Kir subunits. The ATP-sensitive K⁺ channels are made by the octameric association of four Kir6.x subunits with four sulfonylurea receptors (SUR) containing nucleotide-binding domains (NBD). The voltage-dependent K⁺ channel Kv1.1 is expressed in neurons, but a number of EA1 patients may present with predominant muscular phenotypes. The pathogenicity of the K⁺ channel auxiliary subunit MirP2 in hypoPP is still debated.

Figure 4

Pathomechanisms of CLCN1-related myotonia congenita (MC). (A) Presumed mechanism of inheritance in MC. The ClC-1 channel is a dimeric protein with a double barrel-like structure: two subunits assemble to form two parallel ion-conducting pores. In the case of heterozygosity, wild-type (WT) and mutated (MUT) ClC-1 subunits can assemble as homodimers, WT–WT and MUT–MUT, and heterodimers (WT–MUT). In autosomal dominant Thomsen’s disease, the mutated subunit is expected to exert a dominant-negative effect (*) on the associated wild-type subunit in the WT–MUT channel. This results in the reduction of sarcolemma chloride conductance (gCl) by more than 50%, leading to muscle fiber hyperexcitability and muscle stiffness. In autosomal recessive Becker’s disease, the recessive mutation is expected to have no effect on the associated WT subunit. The co-expression of the recessive mutation with the wild-type ClC-1 results at maximum in a 50% reduction of the sarcolemmal chloride conductance, which is not enough to cause myotonia. The occurrence of recessive mutations in homozygosity or in compound heterozygosity is required to reduce the sarcolemmal chloride conductance by more than 50% and to induce myotonia. (+: functional ClC-1 subunit, -: impaired ClC-1 subunit). (B). The main molecular defects of ClC-1 mutants associated with MC consist of either a defect in ClC-1 proteostasis (protein synthesis, cell trafficking, or proteolysis) or a defect in ClC-1 channel gating. Knowledge of molecular pathomechanism may guide the development of efficient mutant-targeted pharmacological treatments to restore ClC-1 function.