{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRyanRine receptor 1 (RYR1) encodes the principal sarcoplasmic reticulum calcium release channel in skeletal muscle, which is essential for excitation–contraction coupling and proper muscle function. Its activity is regulated not only by genetic coding but also by alternative splicing and redox‐dependent modifications that affect its channel properties, as evidenced by altered [3H]ryanodine binding and channel gating in aberrantly spliced forms and redox‐modified channels."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPathogenic mutations in RYR1 underlie a diverse spectrum of neuromuscular disorders, including central core disease, multi‐minicore disease, congenital fiber type disproportion, and malignant hyperthermia susceptibility. Several studies have demonstrated that distinct mutations—whether missense, deletions, or splice alterations—can change the channel’s sensitivity to activation, promote Ca2+ leak, or diminish Ca2+ release under physiological stimulation, thereby disrupting Ca2+ homeostasis and ultimately impairing muscle function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEpidemiological studies and advanced muscle imaging reveal that RYR1‐related myopathies are among the most common congenital myopathies. Characteristic patterns on magnetic resonance imaging have been associated with RYR1 mutations, and the clinical spectrum may extend from early‐onset generalized weakness to later‐onset axial myopathy with specific imaging features, highlighting the diagnostic value of integrating genetic testing with radiological assessment."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical function in skeletal muscle, RYR1 has also been implicated in non‐muscle cell signaling. In T lymphocytes, for example, RYR1 contributes to early subcellular Ca2+ signals in response to nicotinic acid adenine dinucleotide phosphate (NAADP), while in skeletal muscle interactions with proteins such as S100A1, calmodulin, and modulators of excitation–contraction coupling (including TRPC3) fine‐tune its function. Moreover, tissue– and development–specific epigenetic mechanisms, including allele silencing, have been described for RYR1, suggesting further layers of regulation that may modify disease expression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFunctional studies highlight that RYR1 mutations exert their deleterious effects by altering Ca2+ dynamics—reducing thresholds for store overload–induced Ca2+ release, changing open probabilities, and influencing both basal and stimulated Ca2+ levels. Such alterations compromise normal Ca2+ signaling in muscle cells, sometimes leading to aberrant cytokine release (e.g., IL-6) and contributing to the pathogenesis of myopathic conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent technological advances—including high-throughput Förster resonance energy transfer (FRET) screening and high-resolution crystallography—have begun to unravel the structural determinants and interacting domains of the RYR1 channel. These studies not only facilitate the detection of novel RYR1 modulators but also deepen our understanding of how specific residues and domains (such as the SPRY2 module) contribute to channel regulation, ion permeation, and interactions with other key proteins in the excitation–contraction machinery."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "29", "end_ref": "37"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Takashi Kimura, Masayuki Nakamori, John D Lueck, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase in myotonic dystrophy type 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddi223"}], "href": "https://doi.org/10.1093/hmg/ddi223"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15972723"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15972723"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "J M Wilmshurst, S Lillis, H Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RYR1 mutations are a common cause of congenital myopathies with central nuclei."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Neurol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ana.22119"}], "href": "https://doi.org/10.1002/ana.22119"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20839240"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20839240"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Paula Aracena-Parks, Sanjeewa A Goonasekera, Charles P Gilman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of cysteines involved in S-nitrosylation, S-glutathionylation, and oxidation to disulfides in ryanodine receptor type 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M600876200"}], "href": "https://doi.org/10.1074/jbc.M600876200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17071618"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17071618"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Gaetano Santulli, Andrew R Marks "}, {"type": "b", "children": [{"type": "t", "text": "Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Mol Pharmacol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2174/1874467208666150507105105"}], "href": "https://doi.org/10.2174/1874467208666150507105105"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25966694"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25966694"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Ana Ferreiro, Nicole Monnier, Norma B Romero, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Neurol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ana.10231"}], "href": "https://doi.org/10.1002/ana.10231"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12112081"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12112081"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "N Dlamini, N C Voermans, S Lillis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuromuscul Disord (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.nmd.2013.03.008"}], "href": "https://doi.org/10.1016/j.nmd.2013.03.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23628358"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23628358"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Mihail G Chelu, Sanjeewa A Goonasekera, William J Durham, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurology (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1212/01.wnl.0000188870.37076.f2"}], "href": "https://doi.org/10.1212/01.wnl.0000188870.37076.f2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16380615"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16380615"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "M Snoeck, B G M van Engelen, B Küsters, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Centronuclear myopathy due to a de novo dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuromuscul Disord (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.nmd.2007.01.016"}], "href": "https://doi.org/10.1016/j.nmd.2007.01.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17376685"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17376685"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "J A Bevilacqua, N Monnier, M Bitoun, et al. 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