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We identified a R1760W\u2010RyR2 mutation located between the N\u2010terminal domain and the central domain of RyR2 in a CPVT patient by DNA sequencing. Recombinant mutant RyR2<jats:sub>\u22122801mcherry<\/jats:sub> plasmid generated by the overlap extension polymerase chain reaction and seamless cloning was transfected in HEK293 cells for the cell model. Single\u2010cell luminal and cytosolic Ca<jats:sup>2+<\/jats:sup> imaging was measured by endoplasmic reticulum (ER) luminal Ca<jats:sup>2+<\/jats:sup>\u2010sensitive protein D1ER and Fura\u20102 AM on a confocal laser scanning microscope, respectively. We found that in RyR2 mutant cells, the propensity for store\u2010overload\u2010induced Ca<jats:sup>2+<\/jats:sup> release (SOICR) was enhanced representing increased Ca<jats:sup>2+<\/jats:sup> oscillations, reduced activation and termination thresholds of spontaneous Ca<jats:sup>2+<\/jats:sup> release; and the sensitivity to cytosolic Ca<jats:sup>2+<\/jats:sup> activation was increased manifesting reduced steady state ER Ca<jats:sup>2+<\/jats:sup> levels. Our results indicated that R1760W\u2010RyR2 mutation induced calcium leak, representing a gain of function. Further, antiarrhythmic drugs propafenone and flecainide significantly suppressed SOICR caused by the R1760W\u2010RyR2 mutation at a concentration of 20\u2009\u03bcM, which was lower than the concentration at which carvedilol suppressed SOICR.<\/jats:p>","DOI":"10.1111\/1440-1681.13722","type":"journal-article","created":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T20:22:28Z","timestamp":1662754948000},"page":"39-49","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A gain of function ryanodine receptor 2 mutation (<scp>R1760W\u2010RyR2<\/scp>) in catecholaminergic polymorphic ventricular tachycardia"],"prefix":"10.1111","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8649-0623","authenticated-orcid":false,"given":"Siyuan","family":"Li","sequence":"first","affiliation":[{"name":"Department of Cardiology, Beijing Tsinghua Changgung Hospital School of Clinical Medicine, Tsinghua University  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7764-124X","authenticated-orcid":false,"given":"Tingting","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Beijing Tsinghua Changgung Hospital School of Clinical Medicine, Tsinghua University  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9887-386X","authenticated-orcid":false,"given":"Jing","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Beijing Tsinghua Changgung Hospital School of Clinical Medicine, Tsinghua University  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1945-0779","authenticated-orcid":false,"given":"Kun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Beijing Tsinghua Changgung Hospital School of Clinical Medicine, Tsinghua University  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0087-2648","authenticated-orcid":false,"given":"Ying","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Beijing Tsinghua Changgung Hospital School of Clinical Medicine, Tsinghua University  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5843-1108","authenticated-orcid":false,"given":"Ping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Beijing Tsinghua Changgung Hospital School of Clinical Medicine, Tsinghua University  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,10,2]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1080\/14728222.2020.1708326"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP276757"},{"key":"e_1_2_11_4_1","author":"Offerhaus JA","year":"2020","journal-title":"Nat Rev Cardiol"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.91.5.1512"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/europace\/eur277"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000020013.73106.D8"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2017.10.036"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.829267"},{"issue":"9","key":"e_1_2_11_10_1","first-page":"1344","article-title":"The role of stress test for predicting genetic mutations and future cardiac events in asymptomatic relatives of catecholaminergic polymorphic ventricular tachycardia probands. 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