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Recent advances in molecular genetics have expanded the spectrum of skeletal muscle disorders associated with ECC-related proteins, including congenital myopathies, malignant hyperthermia susceptibility, exertional rhabdomyolysis, exertional heat illness, and related episodic disorders. Although these disorders have traditionally been classified according to clinical manifestations, pathological findings, and causative genes, accumulating evidence suggests that genetically and clinically heterogeneous disorders converge on overlapping abnormalities in intracellular Ca\u00b2\u207a handling and ECC function. This review provides an integrative overview of ECC-related skeletal muscle disorders from the perspective of shared abnormalities in intracellular Ca\u00b2\u207a handling and the molecular mechanisms that underlie them. We discuss how pathogenic variants affecting the voltage-sensing skeletal muscle L-type calcium channel (CaV1.1), the ryanodine receptor type 1 (RyR1), and other triad-associated proteins disrupt Ca\u00b2\u207a release from the sarcoplasmic reticulum (SR), luminal Ca\u00b2\u207a regulation, and SR Ca\u00b2\u207a reuptake, leading to diverse but partially convergent phenotypes. We also discuss secondary pathological changes associated with chronic intracellular Ca\u00b2\u207a dysregulation, including mitochondrial dysfunction, oxidative stress, and skeletal muscle remodeling. Finally, we present a functional perspective centered on intracellular Ca\u00b2\u207a handling that complements conventional genetic and clinicopathological classifications of ECC-related skeletal muscle disorders.<\/jats:p>","DOI":"10.1038\/s10038-026-01499-2","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T02:57:34Z","timestamp":1786330654000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular genetics of skeletal muscle diseases associated with abnormal excitation\u2013contraction coupling"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6059-3245","authenticated-orcid":false,"given":"Yukari","family":"Endo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"1499_CR1","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1038\/242244a0","volume":"242","author":"MF Schneider","year":"1973","unstructured":"Schneider MF, Chandler WK. 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