{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T22:31:51Z","timestamp":1787783511236,"version":"build-2784847793"},"reference-count":92,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"crossref","award":["RF-2013-02359065"],"award-info":[{"award-number":["RF-2013-02359065"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Telethon Genetic BioBank","award":["GTB12001D"],"award-info":[{"award-number":["GTB12001D"]}]},{"name":"EurobioBank network"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Ryanodine receptor 1-related myopathies (RYR1-RM) are caused by RYR1 gene variants and comprise a wide spectrum of histopathological manifestations. Here, we focus on patients carrying RYR1 variants and muscle histopathology consistent with central core disease (CCD) or multi-minicore disease (MmD). RNA-sequencing analyses of skeletal muscle biopsies obtained from both CCD and MmD patients and from healthy controls were performed to better understand the molecular pathways activated by RYR1 variants. Our analyses revealed that, beyond the well-established role of RYR1 in calcium homeostasis, broader cellular pathways are implicated. In CCD, differentially expressed genes were enriched for pathways related to oxidative stress response, SMAD signalling, and apoptosis, consistent with the role of intracellular calcium dysregulation in promoting mitochondrial dysfunction and cell death. In contrast, MmD patients exhibited enrichment of pathways related to immune activation. This was corroborated by the upregulation of GTPase-regulating genes and the down-regulation of transcriptional repressors such as ZFP36 and ATN1. When considering all RYR1-RM patients collectively, Wnt signalling, immune-related pathways, and oxidative phosphorylation emerged as shared enriched pathways, indicating possible convergent mechanisms across histopathological phenotypes. Our study suggests that complex gene regulation driven by RYR1 variants may be a unifying feature in CCD and MmD, offering new insight into potential therapeutic targets.<\/jats:p>","DOI":"10.3390\/biom15111599","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T10:07:03Z","timestamp":1763114823000},"page":"1599","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["RYR1-Related Myopathies Involve More than Calcium Dysregulation: Insights from Transcriptomic Profiling"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5525-9576","authenticated-orcid":false,"given":"Daniele","family":"Sabbatini","sequence":"first","affiliation":[{"name":"Neuromuscular Unit, Department of Neuroscience, University of Padova, 35128 Padova, Italy"},{"name":"Unit of Biostatistics, Epidemiology, and Public Health, Department of Cardiac, Thoracic, Vascular and Public Health Sciences, University of Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1887-7270","authenticated-orcid":false,"given":"Domenico","family":"Gorgoglione","sequence":"additional","affiliation":[{"name":"Neuromuscular Unit, Department of Neuroscience, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7013-5785","authenticated-orcid":false,"given":"Giovanni","family":"Minervini","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurora","family":"Fusto","sequence":"additional","affiliation":[{"name":"Neuromuscular Unit, Department of Neuroscience, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Suman","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4792-9047","authenticated-orcid":false,"given":"Chiara","family":"Romualdi","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Vianello","sequence":"additional","affiliation":[{"name":"Neuromuscular Unit, Department of Neuroscience, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0454-2464","authenticated-orcid":false,"given":"Giuliana","family":"Capece","sequence":"additional","affiliation":[{"name":"Neuromuscular Unit, Department of Neuroscience, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianni","family":"Sorar\u00f9","sequence":"additional","affiliation":[{"name":"Neuromuscular Unit, Department of Neuroscience, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2290-6845","authenticated-orcid":false,"given":"Caterina","family":"Marchioretti","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy"},{"name":"Venetian Institute of Molecular Medicine (VIMM), 35129 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8634-0767","authenticated-orcid":false,"given":"Maria","family":"Pennuto","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy"},{"name":"Venetian Institute of Molecular Medicine (VIMM), 35129 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4847-2333","authenticated-orcid":false,"given":"Luca","family":"Vedovelli","sequence":"additional","affiliation":[{"name":"Unit of Biostatistics, Epidemiology, and Public Health, Department of Cardiac, Thoracic, Vascular and Public Health Sciences, University of Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3006-3577","authenticated-orcid":false,"given":"Gyorgy","family":"Szabadkai","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy"},{"name":"Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3075-6525","authenticated-orcid":false,"given":"Luca","family":"Bello","sequence":"additional","affiliation":[{"name":"Neuromuscular Unit, Department of Neuroscience, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7740-4156","authenticated-orcid":false,"given":"Elena","family":"Pegoraro","sequence":"additional","affiliation":[{"name":"Neuromuscular Unit, Department of Neuroscience, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1002\/ana.22510","article-title":"Prevalence of Congenital Myopathies in a Representative Pediatric United States 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