{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T03:23:09Z","timestamp":1764904989774,"version":"3.41.2"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T00:00:00Z","timestamp":1689724800000},"content-version":"vor","delay-in-days":18,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82070329","81870246","81800303","81900292"],"award-info":[{"award-number":["82070329","81870246","81800303","81900292"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanghai Sailing Program","award":["19YF1438000"],"award-info":[{"award-number":["19YF1438000"]}]},{"name":"Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine","award":["ZYYCXTD-C-202207"],"award-info":[{"award-number":["ZYYCXTD-C-202207"]}]},{"DOI":"10.13039\/501100004829","name":"Science and Technology Department of Sichuan Province","doi-asserted-by":"publisher","award":["2022YFS0613","2022YFS0618"],"award-info":[{"award-number":["2022YFS0613","2022YFS0618"]}],"id":[{"id":"10.13039\/501100004829","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,7,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>The ryanodine receptor 2 (RyR2) is essential for cardiac muscle excitation\u2013contraction coupling; dysfunctional RyR2 participates in the development of inherited arrhythmogenic cardiac disease. In this study, a novel RyR2 mutation A690E is identified from a patient with family inheritance of sudden cardiac death, and we aimed to investigate the pathogenic basis of the mutation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>We generated a mouse model that carried the A690E mutation. Mice were characterized by adrenergic-induced ventricular arrhythmias similar to clinical manifestation of the patient. Optical mapping studies revealed that isolated A690E hearts were prone to arrhythmogenesis and displayed frequency-dependence calcium transient alternans. Upon \u03b2-adrenoceptor challenge, the concordant alternans was shifted towards discordant alternans that favour triggering ectopic beats and Ca2+ re-entry; similar phenomenon was also found in the A690E cardiomyocytes. In addition, we found that A690E cardiomyocytes manifested abnormal Ca2+ release and electrophysiological disorders, including an increased sensitivity to cytosolic Ca2+, an elevated diastolic RyR2-mediated Ca2+ leak, and an imbalance between Ca2+ leak and reuptake. Structural analyses reveal that the mutation directly impacts RyR2\u2013FK506 binding protein interaction.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>In this study, we have identified a novel mutation in RyR2 that is associated with sudden cardiac death. By characterizing the function defects of mutant RyR2 in animal, whole heat, and cardiomyocytes, we demonstrated the pathogenic basis of the disease-causing mutation and provided a deeper mechanistic understanding of a life-threatening cardiac arrhythmia.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/europace\/euad220","type":"journal-article","created":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T13:24:48Z","timestamp":1689773088000},"source":"Crossref","is-referenced-by-count":3,"title":["Arrhythmogenic mechanism of a novel ryanodine receptor mutation underlying sudden cardiac death"],"prefix":"10.1093","volume":"25","author":[{"given":"Yunyun","family":"Qian","sequence":"first","affiliation":[{"name":"Department of Cardiology, Shanghai Tenth People\u2019s Hospital, Tongji University School of Medicine , 301 Middle Yanchang Road, Jingan District, Shanghai 200072 , China"},{"name":"Pan-Vascular Research Institute, Heart, Lung, and Blood Center, Tongji University 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China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4618-9745","authenticated-orcid":false,"given":"Yawen","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Electrophysiology, Institute of Cardiovascular Research, Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Southwest Medical University , 1 Xianglin Road, Longmatan District, Luzhou 646000 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7085-2098","authenticated-orcid":false,"given":"Ping","family":"Liu","sequence":"additional","affiliation":[{"name":"National Traditional Chinese Medicine Clinical Research Base and Department of Cardiovascular Medicine of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University , 182 Chunhui Road, Longmatan District, Luzhou 646000 , 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