{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T13:10:14Z","timestamp":1779196214646,"version":"3.51.4"},"reference-count":61,"publisher":"American Society for Clinical Investigation","issue":"7","funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["14PRE19500012"],"award-info":[{"award-number":["14PRE19500012"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["HL055438,HL120108,HL134344"],"award-info":[{"award-number":["HL055438,HL120108,HL134344"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000871","name":"Mayo Clinic","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000871","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,4,4]]},"abstract":"<jats:p>\n                    Hypertrophic cardiomyopathy (HCM) is triggered mainly by mutations in genes encoding sarcomeric proteins, but a significant proportion of patients lack a genetic diagnosis. We identified a potentially novel mutation in ryanodine receptor 2, RyR2-P1124L, in a patient from a genotype-negative HCM cohort. The aim of this study was to determine whether RyR2-P1124L triggers functional and structural alterations in isolated RyR2 channels and whole hearts. We found that P1124L induces significant conformational changes in the SPRY2 domain of RyR2. Recombinant RyR2-P1124L channels displayed a cytosolic loss-of-function phenotype, which contrasted with a higher sensitivity to luminal [Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ], indicating a luminal gain of function. Homozygous mice for RyR2-P1124L showed mild cardiac hypertrophy, similar to the human patient. This phenotype, evident at 1 year of age, was accompanied by an increase in the expression of calmodulin (CaM). P1124L mice also showed higher susceptibility to arrhythmia at 8 months of age, before the onset of hypertrophy. RyR2-P1124L has a distinct cytosolic loss-of-function and a luminal gain-of-function phenotype. This bifunctionally divergent behavior triggers arrhythmias and structural cardiac remodeling, and it involves overexpression of CaM as a potential hypertrophic mediator. This study is relevant to continue elucidating the possible causes of genotype-negative HCM and the role of RyR2 in cardiac hypertrophy.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.126544","type":"journal-article","created":{"date-parts":[[2019,3,5]],"date-time":"2019-03-05T12:06:41Z","timestamp":1551787601000},"source":"Crossref","is-referenced-by-count":28,"title":["Cardiac hypertrophy and arrhythmia in mice induced by a mutation in ryanodine receptor 2"],"prefix":"10.1172","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0552-9029","authenticated-orcid":true,"given":"Francisco J.","family":"Alvarado","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Cardiovascular Medicine, and Cardiovascular Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Martijn","family":"Bos","sequence":"additional","affiliation":[{"name":"Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, and"},{"name":"Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomic Laboratory, Mayo Clinic, Rochester, Minnesota, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2595-9106","authenticated-orcid":true,"given":"Zhiguang","family":"Yuchi","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1224-3088","authenticated-orcid":true,"given":"Carmen 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