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Some mutations impair the gating and thus cause muscle disease. The RyR1 mutation T4706M is linked to a myopathy characterized by muscle weakness. Although, low expression of the T4706M RyR1 protein can explain in part the symptoms, little is known about the function RyR1 channels with this mutation. In order to learn whether this mutation alters channel function in a manner that can account for the observed symptoms, we examined RyR1 channels isolated from mice homozygous for the T4709M (TM) mutation at the single channel level. Ligands, including Ca<jats:sup>2+<\/jats:sup>, ATP, Mg<jats:sup>2+<\/jats:sup> and the RyR inhibitor dantrolene were tested. The full conductance of the TM channel was the same as that of wild type (wt) channels and a population of partial open (subconductive) states were not observed. However, two unique sub-populations of TM RyRs were identified. One half of the TM channels exhibited high open probability at low (100\u00a0nM) and high (50\u00a0\u03bcM) cytoplasmic [Ca<jats:sup>2+<\/jats:sup>], resulting in Ca<jats:sup>2+<\/jats:sup>-insensitive, constitutively high P<jats:sub>o<\/jats:sub> channels. The rest of the TM channels exhibited significantly lower activity within the physiologically relevant range of cytoplasmic [Ca<jats:sup>2+<\/jats:sup>], compared to wt. TM channels retained normal Mg<jats:sup>2+<\/jats:sup> block, modulation by ATP, and inhibition by dantrolene. Together, these results suggest that the TM mutation results in a combination of primary and secondary RyR1 dysfunctions that contribute to disease pathogenesis.<\/jats:p>","DOI":"10.1038\/s41598-023-41801-2","type":"journal-article","created":{"date-parts":[[2023,9,5]],"date-time":"2023-09-05T17:02:03Z","timestamp":1693933323000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Function of a mutant ryanodine receptor (T4709M) linked to congenital myopathy"],"prefix":"10.1038","volume":"13","author":[{"given":"Zsuzsanna \u00c9.","family":"Magyar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judit","family":"Hevesi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Groom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert T.","family":"Dirksen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e1nos","family":"Alm\u00e1ssy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,9,5]]},"reference":[{"key":"41801_CR1","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1152\/physrev.00013.2002","volume":"82","author":"M Fill","year":"2002","unstructured":"Fill, M. & Copello, J. 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