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Here, we generated a knock-in mouse model based on a human gain-of-function mutation which results in a severe, early-onset form of TAM, by inducing a glycine-to-serine point mutation in the ORAI1 pore (\n                    <jats:italic>Orai1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>G100S\/+<\/jats:italic>\n                    <\/jats:sup>\n                    or GS mice). By 8 months of age, GS mice exhibited significant muscle weakness, exercise intolerance, elevated CK levels, hypocalcemia, and robust TA presence. Unexpectedly, constitutive Ca\n                    <jats:sup>2+<\/jats:sup>\n                    entry in mutant mice was observed in muscle only during early development and was abolished in adult skeletal muscle, partly due to reduced ORAI1 expression. Consistent with proteomic results, significant mitochondrial damage and dysfunction was observed in skeletal muscle of GS mice. Thus, GS mice represent a powerful model for investigation of the pathophysiological mechanisms that underlie key TAM symptoms, as well as those compensatory responses that limit the damaging effects of uncontrolled ORAI1-mediated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx.\n                  <\/jats:p>","DOI":"10.1038\/s44318-024-00273-4","type":"journal-article","created":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T13:04:08Z","timestamp":1729170248000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["An Orai1 gain-of-function tubular aggregate myopathy mouse model phenocopies key features of the human disease"],"prefix":"10.1038","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7911-8957","authenticated-orcid":false,"given":"Nan","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0720-3009","authenticated-orcid":false,"given":"Antonio","family":"Michelucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1197-7813","authenticated-orcid":false,"given":"Laura","family":"Pietrangelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1048-4582","authenticated-orcid":false,"given":"Sundeep","family":"Malik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Groom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Leigh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas N","family":"O\u2019Connor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Takano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3997-7436","authenticated-orcid":false,"given":"Paul D","family":"Kingsley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7324-1049","authenticated-orcid":false,"given":"James","family":"Palis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Boncompagni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0213-7591","authenticated-orcid":false,"given":"Feliciano","family":"Protasi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3182-1755","authenticated-orcid":false,"given":"Robert T","family":"Dirksen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,17]]},"reference":[{"key":"273_CR1","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.ceca.2014.11.002","volume":"57","author":"A Ainbinder","year":"2015","unstructured":"Ainbinder A, Boncompagni S, Protasi F, Dirksen RT (2015) Role of Mitofusin-2 in mitochondrial localization and calcium uptake in skeletal muscle. 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