{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T13:06:38Z","timestamp":1779195998909,"version":"3.51.4"},"reference-count":27,"publisher":"American Society for Clinical Investigation","issue":"15","license":[{"start":{"date-parts":[[2020,8,6]],"date-time":"2020-08-06T00:00:00Z","timestamp":1596672000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000871","name":"Mayo Clinic","doi-asserted-by":"crossref","award":["not applicable"],"award-info":[{"award-number":["not applicable"]}],"id":[{"id":"10.13039\/100000871","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000871","name":"Mayo Clinic","doi-asserted-by":"crossref","award":["not applicable"],"award-info":[{"award-number":["not applicable"]}],"id":[{"id":"10.13039\/100000871","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,8,6]]},"abstract":"<jats:p>\n                    We identified a potentially novel homozygous duplication involving the promoter region and exons 1\u20134 of the gene encoding type 2 cardiac ryanodine receptor (\n                    <jats:italic>RYR2<\/jats:italic>\n                    ) that is responsible for highly penetrant, exertion-related sudden deaths\/cardiac arrests in the Amish community without an overt phenotype to suggest\n                    <jats:italic>RYR2-<\/jats:italic>\n                    mediated catecholaminergic polymorphic ventricular tachycardia (CPVT). Homozygous RYR2 duplication (RYR2-DUP) induced pluripotent stem cell cardiomyocytes (iPSC-CMs) were generated from 2 unrelated patients. There was no difference in baseline Ca\n                    <jats:sup>2+<\/jats:sup>\n                    handling measurements between WT-iPSC-CM and RYR2-DUP-iPSC-CM lines. However, compared with WT-iPSC-CMs, both patient lines demonstrated a dramatic reduction in caffeine-stimulated and isoproterenol-stimulated (ISO-stimulated) Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transient amplitude, suggesting RyR2 loss of function. There was a greater than 50% reduction in\n                    <jats:italic>RYR2<\/jats:italic>\n                    transcript\/RyR2 protein expression in both patient iPSC-CMs compared with WT. Delayed afterdepolarization was observed in the RYR2-DUP-iPSC-CMs but not in the WT-iPSC-CMs. Compared with WT-iPSC-CMs, there was significantly elevated arrhythmic activity in the RYR2-DUP-iPSC-CMs in response to ISO. Nadolol, propranolol, and flecainide reduced erratic activity by 8.5-fold, 6.8-fold, and 2.4-fold, respectively, from ISO challenge. Unlike the gain-of-function mechanism observed in\n                    <jats:italic>RYR2-<\/jats:italic>\n                    mediated CPVT, the homozygous multiexon duplication precipitated a dramatic reduction in\n                    <jats:italic>RYR2<\/jats:italic>\n                    transcription and RyR2 protein translation, a loss of function in calcium handling, and a calcium-induced calcium release apparatus that is insensitive to catecholamines and caffeine.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.135952","type":"journal-article","created":{"date-parts":[[2020,7,14]],"date-time":"2020-07-14T12:01:21Z","timestamp":1594728081000},"source":"Crossref","is-referenced-by-count":21,"title":["Molecular characterization of the calcium release channel deficiency syndrome"],"prefix":"10.1172","volume":"5","author":[{"given":"David J.","family":"Tester","sequence":"first","affiliation":[{"name":"Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology and Experimental Therapeutics; Division of Heart Rhythm Services, Department of Cardiovascular Medicine; and Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"CS John","family":"Kim","sequence":"additional","affiliation":[{"name":"Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology and Experimental Therapeutics; Division of Heart Rhythm Services, Department of Cardiovascular Medicine; and Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha K.","family":"Hamrick","sequence":"additional","affiliation":[{"name":"Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology and Experimental Therapeutics; Division of Heart Rhythm Services, Department of Cardiovascular Medicine; and Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Ye","sequence":"additional","affiliation":[{"name":"Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology and Experimental Therapeutics; Division of Heart Rhythm Services, Department of Cardiovascular Medicine; and Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bailey J.","family":"O\u2019Hare","sequence":"additional","affiliation":[{"name":"Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology and Experimental Therapeutics; Division of Heart Rhythm Services, Department of Cardiovascular Medicine; and Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah M.","family":"Bombei","sequence":"additional","affiliation":[{"name":"Division of Cardiology, University of Iowa Stead Family Children\u2019s Hospital, Iowa City, Iowa, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1655-4625","authenticated-orcid":true,"given":"Kristi K.","family":"Fitzgerald","sequence":"additional","affiliation":[{"name":"Nemours Cardiac Center, Nemours\/Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carla M.","family":"Haglund-Turnquist","sequence":"additional","affiliation":[{"name":"Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology and Experimental Therapeutics; Division of Heart Rhythm Services, Department of Cardiovascular Medicine; and Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dianne L.","family":"Atkins","sequence":"additional","affiliation":[{"name":"Division of Cardiology, University of Iowa Stead Family Children\u2019s Hospital, Iowa City, Iowa, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis A. Ochoa","family":"Nunez","sequence":"additional","affiliation":[{"name":"Division of Cardiology, University of Iowa Stead Family Children\u2019s Hospital, Iowa City, Iowa, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian","family":"Law","sequence":"additional","affiliation":[{"name":"Division of Cardiology, University of Iowa Stead Family Children\u2019s Hospital, Iowa City, Iowa, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joel","family":"Temple","sequence":"additional","affiliation":[{"name":"Nemours Cardiac Center, Nemours\/Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Ackerman","sequence":"additional","affiliation":[{"name":"Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology and Experimental Therapeutics; Division of Heart Rhythm Services, Department of Cardiovascular Medicine; and Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"232","published-online":{"date-parts":[[2020,8,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.310083"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.91.5.1512"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2009.08.022"},{"key":"B4"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2019.5400"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000020013.73106.D8"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.pcad.2007.10.005"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.711606"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-10-12"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0095615"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/europace\/eut382"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1419795112"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jelectrocard.2016.09.006"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2016.10.015"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0706573104"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e318149e1e3"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2008.05.033"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2010.06.022"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0163514"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1159\/000184688"},{"key":"B21","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.31683","article-title":"Transcription-factor-dependent enhancer transcription defines a gene regulatory network for cardiac rhythm","volume":"6","author":"Yang","year":"2017","journal-title":"Elife"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.142651999"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/17.12.3309"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.756973"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000192146.85173.4b"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.pcad.2007.10.005"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2011.01.026"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/135952\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:11:26Z","timestamp":1779192686000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/135952"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,6]]},"references-count":27,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2020,8,6]]},"published-print":{"date-parts":[[2020,8,6]]}},"alternative-id":["10.1172\/jci.insight.135952"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.135952","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,6]]},"article-number":"e135952"}}