{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T05:02:49Z","timestamp":1794114169426,"version":"4.8.0"},"reference-count":140,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004923","name":"AFM-T\u00e9l\u00e9thon","doi-asserted-by":"publisher","award":["20225"],"award-info":[{"award-number":["20225"]}],"id":[{"id":"10.13039\/501100004923","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The regulation of intracellular calcium (Ca<jats:sup>2+<\/jats:sup>) homeostasis is fundamental to maintain normal functions in many cell types. The ryanodine receptor (RyR), the largest intracellular calcium release channel located on the sarco\/endoplasmic reticulum (SR\/ER), plays a key role in the intracellular Ca<jats:sup>2+<\/jats:sup> handling. Abnormal type 2 ryanodine receptor (RyR2) function, associated to mutations (ryanopathies) or pathological remodeling, has been reported, not only in cardiac diseases, but also in neuronal and pancreatic disorders. While animal models and in vitro studies provided valuable contributions to our knowledge on RyR2 dysfunctions, the human cell models derived from patients\u2019 cells offer new hope for improving our understanding of human clinical diseases and enrich the development of great medical advances. We here discuss the current knowledge on RyR2 dysfunctions associated with mutations and post-translational remodeling. We then reviewed the novel human cellular technologies allowing the correlation of patient\u2019s genome with their cellular environment and providing approaches for personalized RyR-targeted therapeutics.<\/jats:p>","DOI":"10.1038\/s41419-021-04337-9","type":"journal-article","created":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T18:02:37Z","timestamp":1635789757000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["\u201cRyanopathies\u201d and RyR2 dysfunctions: can we further decipher them using in vitro human disease models?"],"prefix":"10.1038","volume":"12","author":[{"given":"Yvonne","family":"Sleiman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0264-1787","authenticated-orcid":false,"given":"Alain","family":"Lacampagne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1727-3027","authenticated-orcid":false,"given":"Albano C.","family":"Meli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,1]]},"reference":[{"key":"4337_CR1","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1007\/978-981-10-7757-9_11","volume":"87","author":"G Santulli","year":"2018","unstructured":"Santulli G, Lewis D, des Georges A, Marks AR, Frank J. Ryanodine receptor structure and function in health and disease. Subcell Biochem. 2018;87:329\u201352.","journal-title":"Subcell Biochem"},{"key":"4337_CR2","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1113\/jphysiol.1975.sp011026","volume":"249","author":"A Fabiato","year":"1975","unstructured":"Fabiato A, Fabiato F. Contractions induced by a calcium-triggered release of calcium from the sarcoplasmic reticulum of single skinned cardiac cells. J Physiol. 1975;249:469\u201395.","journal-title":"J Physiol"},{"key":"4337_CR3","doi-asserted-by":"publisher","first-page":"e2102265118","DOI":"10.1073\/pnas.2102265118","volume":"118","author":"P Lobos","year":"2021","unstructured":"Lobos P, C\u00f3rdova A, Vega-V\u00e1squez I, Ram\u00edrez OA, Adasme T, Toledo J, et al. RyR-mediated Ca<sup>2\u2009+\u2009<\/sup> release elicited by neuronal activity induces nuclear Ca<sup>2\u2009+\u2009<\/sup> signals, CREB phosphorylation, and Npas4\/RyR2 expression. Proc Natl Acad Sci. 2021;118:e2102265118.","journal-title":"Proc Natl Acad Sci"},{"key":"4337_CR4","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1161\/01.CIR.103.2.196","volume":"103","author":"SG Priori","year":"2001","unstructured":"Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation. 2001;103:196\u2013200.","journal-title":"Circulation."},{"key":"4337_CR5","doi-asserted-by":"publisher","first-page":"32877","DOI":"10.1074\/jbc.M701418200","volume":"282","author":"S Kim","year":"2007","unstructured":"Kim S, Yun H-M, Baik J-H, Chung KC, Nah S-Y, Rhim H. Functional Interaction of Neuronal Cav1.3 L-type Calcium Channel with Ryanodine Receptor Type 2 in the Rat Hippocampus*. J Biol Chem. 2007;282:32877\u201389.","journal-title":"J Biol Chem"},{"key":"4337_CR6","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1161\/01.CIR.103.4.485","volume":"103","author":"PJ Laitinen","year":"2001","unstructured":"Laitinen PJ, Brown KM, Piippo K, Swan H, Devaney JM, Brahmbhatt B, et al. Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation. 2001;103:485\u201390.","journal-title":"Circulation."},{"key":"4337_CR7","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1093\/hmg\/10.3.189","volume":"10","author":"N Tiso","year":"2001","unstructured":"Tiso N, Stephan DA, Nava A, Bagattin A, Devaney JM, Stanchi F, et al. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet. 2001;10:189\u201394.","journal-title":"Hum Mol Genet"},{"key":"4337_CR8","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1161\/CIRCRESAHA.111.244970","volume":"109","author":"AC Meli","year":"2011","unstructured":"Meli AC, Refaat MM, Dura M, Reiken S, Wronska A, Wojciak J, et al. A novel ryanodine receptor mutation linked to sudden death increases sensitivity to cytosolic calcium. Circ Res. 2011;109:281\u201390.","journal-title":"Circ Res"},{"key":"4337_CR9","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.hrthm.2016.10.015","volume":"14","author":"Y Fujii","year":"2017","unstructured":"Fujii Y, Itoh H, Ohno S, Murayama T, Kurebayashi N, Aoki H, et al. A type 2 ryanodine receptor variant associated with reduced Ca(2+) release and short-coupled torsades de pointes ventricular arrhythmia. Heart Rhythm. 2017;14:98\u2013107.","journal-title":"Heart Rhythm"},{"key":"4337_CR10","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.ijcard.2014.11.119","volume":"180","author":"JW Cheung","year":"2015","unstructured":"Cheung JW, Meli AC, Xie W, Mittal S, Reiken S, Wronska A, et al. Short-coupled polymorphic ventricular tachycardia at rest linked to a novel ryanodine receptor (RyR2) mutation: leaky RyR2 channels under non-stress conditions. Int J Cardiol. 2015;180:228\u201336.","journal-title":"Int J Cardiol"},{"key":"4337_CR11","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1242\/dmm.030320","volume":"10","author":"KO Brandao","year":"2017","unstructured":"Brandao KO, Tabel VA, Atsma DE, Mummery CL, Davis RP. Human pluripotent stem cell models of cardiac disease: from mechanisms to therapies. Dis Model Mech. 2017;10:1039\u201359.","journal-title":"Dis Model Mech"},{"key":"4337_CR12","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1016\/j.molmed.2011.05.001","volume":"17","author":"RP Davis","year":"2011","unstructured":"Davis RP, van den Berg CW, Casini S, Braam SR, Mummery CL. Pluripotent stem cell models of cardiac disease and their implication for drug discovery and development. Trends Mol Med. 2011;17:475\u201384.","journal-title":"Trends Mol Med"},{"key":"4337_CR13","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1161\/CIRCRESAHA.117.305365","volume":"117","author":"I Karakikes","year":"2015","unstructured":"Karakikes I, Ameen M, Termglinchan V, Wu JC. Human induced pluripotent stem cell-derived cardiomyocytes: insights into molecular, cellular, and functional phenotypes. Circ Res. 2015;117:80\u20138.","journal-title":"Circ Res"},{"key":"4337_CR14","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.pharmthera.2013.10.007","volume":"141","author":"N Milani-Nejad","year":"2014","unstructured":"Milani-Nejad N, Janssen PM. Small and large animal models in cardiac contraction research: advantages and disadvantages. Pharm Ther. 2014;141:235\u201349.","journal-title":"Pharm Ther"},{"key":"4337_CR15","doi-asserted-by":"publisher","first-page":"117954681668606","DOI":"10.1177\/1179546816686061","volume":"11","author":"AG Edwards","year":"2017","unstructured":"Edwards AG, Louch WE. Species-dependent mechanisms of cardiac arrhythmia: a cellular focus. Clin Med Insights Cardiol. 2017;11:1179546816686061.","journal-title":"Clin Med Insights Cardiol"},{"key":"4337_CR16","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1161\/CIRCRESAHA.116.309126","volume":"119","author":"PM Janssen","year":"2016","unstructured":"Janssen PM, Biesiadecki BJ, Ziolo MT, Davis JP. The need for speed: mice, men, and myocardial kinetic reserve. Circ Res. 2016;119:418\u201321.","journal-title":"Circ Res"},{"key":"4337_CR17","doi-asserted-by":"publisher","first-page":"512831","DOI":"10.1155\/2014\/512831","volume":"2014","author":"I Acimovic","year":"2014","unstructured":"Acimovic I, Vilotic A, Pesl M, Lacampagne A, Dvorak P, Rotrekl V, et al. Human pluripotent stem cell-derived cardiomyocytes as research and therapeutic tools. Biomed Res Int. 2014;2014:512831.","journal-title":"Biomed Res Int"},{"key":"4337_CR18","doi-asserted-by":"publisher","first-page":"1512","DOI":"10.1161\/01.CIR.91.5.1512","volume":"91","author":"A Leenhardt","year":"1995","unstructured":"Leenhardt A, Lucet V, Denjoy I, Grau F, Ngoc DD, Coumel P. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation 1995;91:1512\u20139.","journal-title":"Circulation"},{"key":"4337_CR19","first-page":"17","volume":"1","author":"A Leenhardt","year":"1999","unstructured":"Leenhardt A, Maison-Blanche P, Denjoy I, Cauchemez B, Joubert JP, Coumel P. [Mechanism of spontaneous occurrence of tachycardia]. Arch Mal Coeur Vaiss. 1999;1:17\u201322.","journal-title":"Arch Mal Coeur Vaiss"},{"key":"4337_CR20","doi-asserted-by":"publisher","first-page":"1652","DOI":"10.1016\/j.hrthm.2009.06.033","volume":"6","author":"M Cerrone","year":"2009","unstructured":"Cerrone M, Napolitano C, Priori SG. Catecholaminergic polymorphic ventricular tachycardia: A paradigm to understand mechanisms of arrhythmias associated to impaired Ca(2+) regulation. Heart Rhythm. 2009;6:1652\u20139.","journal-title":"Heart Rhythm"},{"key":"4337_CR21","unstructured":"Napolitano C, Priori SG, Bloise R. Catecholaminergic Polymorphic Ventricular Tachycardia. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al., editors. GeneReviews((R)): Seattle (WA); 1993."},{"key":"4337_CR22","doi-asserted-by":"publisher","first-page":"11759","DOI":"10.1073\/pnas.1932318100","volume":"100","author":"D Terentyev","year":"2003","unstructured":"Terentyev D, Viatchenko-Karpinski S, Gyorke I, Volpe P, Williams SC, Gyorke S. Calsequestrin determines the functional size and stability of cardiac intracellular calcium stores: Mechanism for hereditary arrhythmia. Proc Natl Acad Sci USA. 2003;100:11759\u201364.","journal-title":"Proc Natl Acad Sci USA"},{"key":"4337_CR23","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1111\/j.1540-8167.2007.00913.x","volume":"18","author":"ZA Bhuiyan","year":"2007","unstructured":"Bhuiyan ZA, Hamdan MA, Shamsi ET, Postma AV, Mannens MM, Wilde AA, et al. A novel early onset lethal form of catecholaminergic polymorphic ventricular tachycardia maps to chromosome 7p14-p22. J Cardiovasc Electrophysiol. 2007;18:1060\u20136.","journal-title":"J Cardiovasc Electrophysiol"},{"key":"4337_CR24","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1016\/j.ajhg.2012.08.015","volume":"91","author":"M Nyegaard","year":"2012","unstructured":"Nyegaard M, Overgaard MT, Sondergaard MT, Vranas M, Behr ER, Hildebrandt LL, et al. Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death. Am J Hum Genet. 2012;91:703\u201312.","journal-title":"Am J Hum Genet"},{"key":"4337_CR25","doi-asserted-by":"publisher","first-page":"2759","DOI":"10.1093\/hmg\/dds104","volume":"21","author":"N Roux-Buisson","year":"2012","unstructured":"Roux-Buisson N, Cacheux M, Fourest-Lieuvin A, Fauconnier J, Brocard J, Denjoy I, et al. Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human. Hum Mol Genet. 2012;21:2759\u201367.","journal-title":"Hum Mol Genet"},{"key":"4337_CR26","doi-asserted-by":"crossref","unstructured":"Cacheux M, Fauconnier J, Thireau J, Osseni A, Brocard J, Roux-Buisson N, et al. Interplay between Triadin and Calsequestrin in the Pathogenesis of CPVT in the Mouse. Mol Ther. 2019;28:171\u20139.","DOI":"10.1016\/j.ymthe.2019.09.012"},{"key":"4337_CR27","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1038\/nature01335","volume":"421","author":"PJ Mohler","year":"2003","unstructured":"Mohler PJ, Schott JJ, Gramolini AO, Dilly KW, Guatimosim S, duBell WH, et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature. 2003;421:634\u20139.","journal-title":"Nature."},{"key":"4337_CR28","doi-asserted-by":"publisher","first-page":"9137","DOI":"10.1073\/pnas.0402546101","volume":"101","author":"PJ Mohler","year":"2004","unstructured":"Mohler PJ, Splawski I, Napolitano C, Bottelli G, Sharpe L, Timothy K, et al. A cardiac arrhythmia syndrome caused by loss of ankyrin-B function. Proc Natl Acad Sci USA. 2004;101:9137\u201342.","journal-title":"Proc Natl Acad Sci USA"},{"key":"4337_CR29","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1161\/CIRCGENETICS.114.000703","volume":"7","author":"H Swan","year":"2014","unstructured":"Swan H, Amarouch MY, Leinonen J, Marjamaa A, Kucera JP, Laitinen-Forsblom PJ, et al. Gain-of-function mutation of the SCN5A gene causes exercise-induced polymorphic ventricular arrhythmias. Circ Cardiovasc Genet. 2014;7:771\u201381.","journal-title":"Circ Cardiovasc Genet"},{"key":"4337_CR30","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1016\/j.hrthm.2014.02.015","volume":"11","author":"MM Kalscheur","year":"2014","unstructured":"Kalscheur MM, Vaidyanathan R, Orland KM, Abozeid S, Fabry N, Maginot KR, et al. KCNJ2 mutation causes an adrenergic-dependent rectification abnormality with calcium sensitivity and ventricular arrhythmia. Heart Rhythm. 2014;11:885\u201394.","journal-title":"Heart Rhythm"},{"key":"4337_CR31","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1161\/CIRCGENETICS.111.962316","volume":"5","author":"H Kimura","year":"2012","unstructured":"Kimura H, Zhou J, Kawamura M, Itoh H, Mizusawa Y, Ding WG, et al. Phenotype variability in patients carrying KCNJ2 mutations. Circ Cardiovasc Genet. 2012;5:344\u201353.","journal-title":"Circ Cardiovasc Genet"},{"key":"4337_CR32","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1016\/S0092-8674(01)00342-7","volume":"105","author":"NM Plaster","year":"2001","unstructured":"Plaster NM, Tawil R, Tristani-Firouzi M, Canun S, Bendahhou S, Tsunoda A, et al. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen\u2019s syndrome. Cell 2001;105:511\u20139.","journal-title":"Cell"},{"key":"4337_CR33","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1016\/j.joa.2015.09.008","volume":"32","author":"N Sumitomo","year":"2016","unstructured":"Sumitomo N. Current topics in catecholaminergic polymorphic ventricular tachycardia. J Arrhythm. 2016;32:344\u201351.","journal-title":"J Arrhythm"},{"key":"4337_CR34","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1016\/S0006-3495(96)79581-4","volume":"70","author":"A Gonzalez","year":"1996","unstructured":"Gonzalez A, Caputo C. Ryanodine interferes with charge movement repriming in amphibian skeletal muscle fibers. Biophysical J. 1996;70:376\u201382.","journal-title":"Biophysical J"},{"key":"4337_CR35","doi-asserted-by":"crossref","unstructured":"Peng W, Shen H, Wu J, Guo W, Pan X, Wang R, et al. Structural basis for the gating mechanism of the type 2 ryanodine receptor RyR2. Science. 2016;354:aah5324 [pii].","DOI":"10.1126\/science.aah5324"},{"key":"4337_CR36","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1161\/CIRCEP.112.970517","volume":"5","author":"C van der Werf","year":"2012","unstructured":"van der Werf C, Nederend I, Hofman N, van Geloven N, Ebink C, Frohn-Mulder IM, et al. Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives. Circ Arrhythm Electrophysiol. 2012;5:748\u201356.","journal-title":"Circ Arrhythm Electrophysiol"},{"key":"4337_CR37","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1042\/BJ20082324","volume":"419","author":"S Zissimopoulos","year":"2009","unstructured":"Zissimopoulos S, Thomas NL, Jamaluddin WW, Lai FA. FKBP12.6 binding of ryanodine receptors carrying mutations associated with arrhythmogenic cardiac disease. Biochem J. 2009;419:273\u20138.","journal-title":"Biochem J"},{"key":"4337_CR38","doi-asserted-by":"crossref","unstructured":"Salvage SC, Gallant EM, Beard NA, Ahmad S, Valli H, Fraser JA, et al. Ion channel gating in cardiac ryanodine receptors from the arrhythmic RyR2-P2328S mouse. J Cell Sci. 2019;132:jcs229039.","DOI":"10.1242\/jcs.229039"},{"key":"4337_CR39","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.1161\/01.RES.0000192146.85173.4b","volume":"97","author":"D Jiang","year":"2005","unstructured":"Jiang D, Wang R, Xiao B, Kong H, Hunt DJ, Choi P, et al. Enhanced store overload-induced Ca2+ release and channel sensitivity to luminal Ca2+ activation are common defects of RyR2 mutations linked to ventricular tachycardia and sudden death. Circ Res. 2005;97:1173\u201381.","journal-title":"Circ Res"},{"key":"4337_CR40","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1007\/s00395-020-0797-z","volume":"115","author":"S Hamilton","year":"2020","unstructured":"Hamilton S, Terentyeva R, Martin B, Perger F, Li J, Stepanov A, et al. Increased RyR2 activity is exacerbated by calcium leak-induced mitochondrial ROS. Basic Res Cardiol. 2020;115:38.","journal-title":"Basic Res Cardiol"},{"key":"4337_CR41","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1001\/jamacardio.2019.5400","volume":"5","author":"DJ Tester","year":"2020","unstructured":"Tester DJ, Bombei HM, Fitzgerald KK, Giudicessi JR, Pitel BA, Thorland EC, et al. Identification of a Novel Homozygous Multi-Exon Duplication in RYR2 Among Children With Exertion-Related Unexplained Sudden Deaths in the Amish Community. JAMA Cardiol. 2020;5:340\u20135.","journal-title":"JAMA Cardiol"},{"key":"4337_CR42","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1038\/s10038-020-0738-6","volume":"65","author":"D Olubando","year":"2020","unstructured":"Olubando D, Hopton C, Eden J, Caswell R, Lowri Thomas N, Roberts SA, et al. Classification and correlation of RYR2 missense variants in individuals with catecholaminergic polymorphic ventricular tachycardia reveals phenotypic relationships. J Hum Genet. 2020;65:531\u20139.","journal-title":"J Hum Genet"},{"key":"4337_CR43","doi-asserted-by":"publisher","first-page":"806","DOI":"10.1016\/S0735-1097(83)80226-5","volume":"2","author":"GN Kay","year":"1983","unstructured":"Kay GN, Plumb VJ, Arciniegas JG, Henthorn RW, Waldo AL. Torsade de pointes: the long-short initiating sequence and other clinical features: observations in 32 patients. J Am Coll Cardiol. 1983;2:806\u201317.","journal-title":"J Am Coll Cardiol"},{"key":"4337_CR44","doi-asserted-by":"publisher","first-page":"2149","DOI":"10.1016\/j.ehj.2004.08.020","volume":"25","author":"T Noda","year":"2004","unstructured":"Noda T, Shimizu W, Satomi K, Suyama K, Kurita T, Aihara N, et al. Classification and mechanism of Torsade de Pointes initiation in patients with congenital long QT syndrome. Eur Heart J. 2004;25:2149\u201354.","journal-title":"Eur Heart J"},{"key":"4337_CR45","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1161\/01.CIR.89.1.206","volume":"89","author":"A Leenhardt","year":"1994","unstructured":"Leenhardt A, Glaser E, Burguera M, Nurnberg M, Maison-Blanche P, Coumel P. Short-coupled variant of torsade de pointes. A new electrocardiographic entity in the spectrum of idiopathic ventricular tachyarrhythmias. Circulation. 1994;89:206\u201315.","journal-title":"Circulation."},{"key":"4337_CR46","doi-asserted-by":"publisher","first-page":"1300","DOI":"10.1016\/j.jacc.2013.09.078","volume":"63","author":"A Mazzanti","year":"2014","unstructured":"Mazzanti A, Kanthan A, Monteforte N, Memmi M, Bloise R, Novelli V, et al. Novel insight into the natural history of short QT syndrome. J Am Coll Cardiol. 2014;63:1300\u20138.","journal-title":"J Am Coll Cardiol"},{"key":"4337_CR47","doi-asserted-by":"publisher","first-page":"e0139058","DOI":"10.1371\/journal.pone.0139058","volume":"10","author":"Z Xiao","year":"2015","unstructured":"Xiao Z, Guo W, Yuen SM, Wang R, Zhang L, Van Petegem F, et al. The H29D mutation does not enhance cytosolic Ca2+ activation of the cardiac ryanodine receptor. PLoS ONE. 2015;10:e0139058.","journal-title":"PLoS ONE"},{"key":"4337_CR48","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/j.ijcard.2016.11.052","volume":"227","author":"M Kimura","year":"2017","unstructured":"Kimura M, Fujisawa T, Aizawa Y, Matsuhashi N, Ito S, Nakajima K, et al. An RyR2 mutation found in a family with a short-coupled variant of torsade de pointes. Int J Cardiol. 2017;227:367\u20139.","journal-title":"Int J Cardiol"},{"key":"4337_CR49","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.psym.2017.10.009","volume":"59","author":"SR Beach","year":"2018","unstructured":"Beach SR, Celano CM, Sugrue AM, Adams C, Ackerman MJ, Noseworthy PA, et al. QT Prolongation, Torsades de Pointes, and Psychotropic Medications: A 5-Year Update. Psychosomatics. 2018;59:105\u201322.","journal-title":"Psychosomatics."},{"key":"4337_CR50","doi-asserted-by":"publisher","DOI":"10.1186\/s13256-018-1825-6","volume":"12","author":"LK Seidlmayer","year":"2018","unstructured":"Seidlmayer LK, Riediger F, Pagonas N, Nordbeck P, Ritter O, Sasko B. Description of a novel RyR2 mutation in a juvenile patient with symptomatic catecholaminergic polymorphic ventricular tachycardia in sleep and during exercise: a case report. J Med Case Rep. 2018;12:298.","journal-title":"J Med Case Rep"},{"key":"4337_CR51","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1042\/BSR20210209","volume":"41","author":"X Zhong","year":"2021","unstructured":"Zhong X, Guo W, Wei J, Tang Y, Liu Y, Zhang JZ, et al. Identification of loss-of-function RyR2 mutations associated with idiopathic ventricular fibrillation and sudden death. Biosci Rep. 2021;41:4.","journal-title":"Biosci Rep"},{"key":"4337_CR52","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1016\/j.ajhg.2009.02.009","volume":"84","author":"M Alders","year":"2009","unstructured":"Alders M, Koopmann TT, Christiaans I, Postema PG, Beekman L, Tanck MW, et al. Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation. Am J Hum Genet. 2009;84:468\u201376.","journal-title":"Am J Hum Genet"},{"key":"4337_CR53","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1161\/CIRCEP.110.959619","volume":"4","author":"S Ohno","year":"2011","unstructured":"Ohno S, Zankov DP, Ding WG, Itoh H, Makiyama T, Doi T, et al. KCNE5 (KCNE1L) variants are novel modulators of Brugada syndrome and idiopathic ventricular fibrillation. Circ Arrhythm Electrophysiol. 2011;4:352\u201361.","journal-title":"Circ Arrhythm Electrophysiol"},{"key":"4337_CR54","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1093\/eurheartj\/ehv449","volume":"37","author":"A Koizumi","year":"2016","unstructured":"Koizumi A, Sasano T, Kimura W, Miyamoto Y, Aiba T, Ishikawa T, et al. Genetic defects in a His-Purkinje system transcription factor, IRX3, cause lethal cardiac arrhythmias. Eur Heart J. 2016;37:1469\u201375.","journal-title":"Eur Heart J"},{"key":"4337_CR55","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1161\/01.CIR.94.5.983","volume":"94","author":"C Basso","year":"1996","unstructured":"Basso C, Thiene G, Corrado D, Angelini A, Nava A, Valente M. Arrhythmogenic right ventricular cardiomyopathy. Dysplasia, dystrophy, or myocarditis?. Circulation. 1996;94:983\u201391.","journal-title":"Circulation"},{"key":"4337_CR56","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1146\/annurev.med.052208.130419","volume":"61","author":"S Sen-Chowdhry","year":"2010","unstructured":"Sen-Chowdhry S, Morgan RD, Chambers JC, McKenna WJ. Arrhythmogenic cardiomyopathy: etiology, diagnosis, and treatment. Annu Rev Med. 2010;61:233\u201353.","journal-title":"Annu Rev Med"},{"key":"4337_CR57","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1038\/ncpcardio1182","volume":"5","author":"MM Awad","year":"2008","unstructured":"Awad MM, Calkins H, Judge DP. Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia\/cardiomyopathy. Nat Clin Pr Cardiovasc Med. 2008;5:258\u201367.","journal-title":"Nat Clin Pr Cardiovasc Med"},{"key":"4337_CR58","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1016\/j.bbamem.2007.07.014","volume":"1778","author":"D Garrod","year":"2008","unstructured":"Garrod D, Chidgey M. Desmosome structure, composition and function. Biochim Biophys Acta. 2008;1778:572\u201387.","journal-title":"Biochim Biophys Acta"},{"key":"4337_CR59","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1016\/j.cardiores.2004.10.005","volume":"65","author":"G Beffagna","year":"2005","unstructured":"Beffagna G, Occhi G, Nava A, Vitiello L, Ditadi A, Basso C, et al. Regulatory mutations in transforming growth factor-beta3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1. Cardiovasc Res. 2005;65:366\u201373.","journal-title":"Cardiovasc Res"},{"key":"4337_CR60","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1016\/j.ajhg.2008.01.010","volume":"82","author":"ND Merner","year":"2008","unstructured":"Merner ND, Hodgkinson KA, Haywood AF, Connors S, French VM, Drenckhahn JD, et al. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet. 2008;82:809\u201321.","journal-title":"Am J Hum Genet"},{"key":"4337_CR61","doi-asserted-by":"publisher","first-page":"4595","DOI":"10.1093\/hmg\/ddq387","volume":"19","author":"B Klauke","year":"2010","unstructured":"Klauke B, Kossmann S, Gaertner A, Brand K, Stork I, Brodehl A, et al. De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy. Hum Mol Genet. 2010;19:4595\u2013607.","journal-title":"Hum Mol Genet"},{"key":"4337_CR62","doi-asserted-by":"publisher","first-page":"1128","DOI":"10.1093\/eurheartj\/ehr451","volume":"33","author":"G Quarta","year":"2012","unstructured":"Quarta G, Syrris P, Ashworth M, Jenkins S, Zuborne Alapi K, Morgan J, et al. Mutations in the Lamin A\/C gene mimic arrhythmogenic right ventricular cardiomyopathy. Eur Heart J. 2012;33:1128\u201336.","journal-title":"Eur Heart J"},{"key":"4337_CR63","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1007\/s00439-010-0855-y","volume":"128","author":"KM Meurs","year":"2010","unstructured":"Meurs KM, Mauceli E, Lahmers S, Acland GM, White SN, Lindblad-Toh K. Genome-wide association identifies a deletion in the 3\u2019 untranslated region of striatin in a canine model of arrhythmogenic right ventricular cardiomyopathy. Hum Genet. 2010;128:315\u201324.","journal-title":"Hum Genet"},{"key":"4337_CR64","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1161\/CIRCULATIONAHA.110.005405","volume":"124","author":"M Taylor","year":"2011","unstructured":"Taylor M, Graw S, Sinagra G, Barnes C, Slavov D, Brun F, et al. Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes. Circulation. 2011;124:876\u201385.","journal-title":"Circulation."},{"key":"4337_CR65","unstructured":"Nava A, Martini B, Thiene G, Buja GF, Canciani B, Scognamiglio R, et al. [Arrhythmogenic right ventricular dysplasia. Study of a selected population]. G Ital Cardiol. 1988;18:2\u20139."},{"key":"4337_CR66","doi-asserted-by":"publisher","first-page":"2151","DOI":"10.1093\/hmg\/4.11.2151","volume":"4","author":"A Rampazzo","year":"1995","unstructured":"Rampazzo A, Nava A, Erne P, Eberhard M, Vian E, Slomp P, et al. A new locus for arrhythmogenic right ventricular cardiomyopathy (ARVD2) maps to chromosome 1q42-q43. Hum Mol Genet. 1995;4:2151\u20134.","journal-title":"Hum Mol Genet"},{"key":"4337_CR67","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1093\/hmg\/10.3.189","volume":"10","author":"N Tiso","year":"2001","unstructured":"Tiso N, Stephan DA, Nava A, Bagattin A, Devaney JM, Stanchi F, et al. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet. 2001;10:189\u201394.","journal-title":"Hum Mol Genet"},{"key":"4337_CR68","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1016\/S0006-291X(02)02689-X","volume":"299","author":"N Tiso","year":"2002","unstructured":"Tiso N, Salamon M, Bagattin A, Danieli GA, Argenton F, Bortolussi M. The binding of the RyR2 calcium channel to its gating protein FKBP12.6 is oppositely affected by ARVD2 and VTSIP mutations. Biochem Biophys Res Commun. 2002;299:594\u20138.","journal-title":"Biochem Biophys Res Commun"},{"key":"4337_CR69","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.cardiores.2004.07.023","volume":"64","author":"NL Thomas","year":"2004","unstructured":"Thomas NL, George CH, Lai FA. Functional heterogeneity of ryanodine receptor mutations associated with sudden cardiac death. Cardiovasc Res. 2004;64:52\u201360.","journal-title":"Cardiovasc Res"},{"key":"4337_CR70","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1093\/cvr\/cvu240","volume":"105","author":"M Seidel","year":"2015","unstructured":"Seidel M, Thomas NL, Williams AJ, Lai FA, Zissimopoulos S. Dantrolene rescues aberrant N-terminus intersubunit interactions in mutant pro-arrhythmic cardiac ryanodine receptors. Cardiovasc Res. 2015;105:118\u201328.","journal-title":"Cardiovasc Res"},{"key":"4337_CR71","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/S0735-1097(02)01946-0","volume":"40","author":"B Bauce","year":"2002","unstructured":"Bauce B, Rampazzo A, Basso C, Bagattin A, Daliento L, Tiso N, et al. Screening for ryanodine receptor type 2 mutations in families with effort-induced polymorphic ventricular arrhythmias and sudden death: early diagnosis of asymptomatic carriers. J Am Coll Cardiol. 2002;40:341\u20139.","journal-title":"J Am Coll Cardiol"},{"key":"4337_CR72","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1016\/j.cardiores.2006.04.004","volume":"71","author":"H Milting","year":"2006","unstructured":"Milting H, Lukas N, Klauke B, Korfer R, Perrot A, Osterziel KJ, et al. Composite polymorphisms in the ryanodine receptor 2 gene associated with arrhythmogenic right ventricular cardiomyopathy. Cardiovasc Res. 2006;71:496\u2013505.","journal-title":"Cardiovasc Res"},{"key":"4337_CR73","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1007\/s00439-006-0193-2","volume":"120","author":"KM Meurs","year":"2006","unstructured":"Meurs KM, Lacombe VA, Dryburgh K, Fox PR, Reiser PR, Kittleson MD. Differential expression of the cardiac ryanodine receptor in normal and arrhythmogenic right ventricular cardiomyopathy canine hearts. Hum Genet. 2006;120:111\u20138.","journal-title":"Hum Genet"},{"key":"4337_CR74","doi-asserted-by":"publisher","first-page":"1999","DOI":"10.1016\/j.hrthm.2014.07.020","volume":"11","author":"N Roux-Buisson","year":"2014","unstructured":"Roux-Buisson N, Gandjbakhch E, Donal E, Probst V, Deharo JC, Chevalier P, et al. Prevalence and significance of rare RYR2 variants in arrhythmogenic right ventricular cardiomyopathy\/dysplasia: results of a systematic screening. Heart Rhythm. 2014;11:1999\u20132009.","journal-title":"Heart Rhythm"},{"key":"4337_CR75","unstructured":"Fujino N, Ino H, Hayashi K, Uchiyama K, Nagata M, Konno T, et al. Abstract 915: A Novel Missense Mutation in Cardiac Ryanodine Receptor Gene as a Possible Cause of Hypertrophic Cardiomyopathy: Evidence From Familial Analysis. Circulation. 2006;114:II_165-II_."},{"key":"4337_CR76","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1161\/CIRCRESAHA.111.256560","volume":"110","author":"Y Tang","year":"2012","unstructured":"Tang Y, Tian X, Wang R, Fill M, Chen SR. Abnormal termination of Ca2+ release is a common defect of RyR2 mutations associated with cardiomyopathies. Circ Res. 2012;110:968\u201377.","journal-title":"Circ Res"},{"key":"4337_CR77","doi-asserted-by":"publisher","first-page":"eabb2964","DOI":"10.1126\/sciadv.abb2964","volume":"6","author":"KA Iyer","year":"2020","unstructured":"Iyer KA, Hu Y, Nayak AR, Kurebayashi N, Murayama T, Sams\u00f3 M. Structural mechanism of two gain-of-function cardiac and skeletal RyR mutations at an equivalent site by cryo-EM. Sci Adv. 2020;6:eabb2964.","journal-title":"Sci Adv"},{"key":"4337_CR78","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1083\/jcb.128.5.893","volume":"128","author":"G Giannini","year":"1995","unstructured":"Giannini G, Conti A, Mammarella S, Scrobogna M, Sorrentino V. The ryanodine receptor\/calcium channel genes are widely and differentially expressed in murine brain and peripheral tissues. J Cell Biol. 1995;128:893\u2013904.","journal-title":"J Cell Biol"},{"key":"4337_CR79","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1038\/emboj.2010.279","volume":"30","author":"E Ziviani","year":"2011","unstructured":"Ziviani E, Lippi G, Bano D, Munarriz E, Guiducci S, Zoli M, et al. Ryanodine receptor-2 upregulation and nicotine-mediated plasticity. EMBO J. 2011;30:194\u2013204.","journal-title":"EMBO J"},{"key":"4337_CR80","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1089\/ars.2017.7277","volume":"29","author":"JY More","year":"2018","unstructured":"More JY, Bruna BA, Lobos PE, Galaz JL, Figueroa PL, Namias S, et al. Calcium release mediated by redox-sensitive RyR2 channels has a central role in hippocampal structural plasticity and spatial memory. Antioxid Redox Signal. 2018;29:1125\u201346.","journal-title":"Antioxid Redox Signal"},{"key":"4337_CR81","first-page":"2230","volume":"118","author":"SE Lehnart","year":"2008","unstructured":"Lehnart SE, Mongillo M, Bellinger A, Lindegger N, Chen BX, Hsueh W, et al. Leaky Ca2+ release channel\/ryanodine receptor 2 causes seizures and sudden cardiac death in mice. J Clin Investig. 2008;118:2230\u201345.","journal-title":"J Clin Investig"},{"key":"4337_CR82","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1097\/NRL.0b013e3181ef0d52","volume":"17","author":"T Nagrani","year":"2011","unstructured":"Nagrani T, Siyamwala M, Vahid G, Bekheit S. Ryanodine calcium channel: a novel channelopathy for seizures. Neurologist. 2011;17:91\u20134.","journal-title":"Neurologist"},{"key":"4337_CR83","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.seizure.2019.02.017","volume":"67","author":"SM Yap","year":"2019","unstructured":"Yap SM, Smyth S. Ryanodine receptor 2 (RYR2) mutation: A potentially novel neurocardiac calcium channelopathy manifesting as primary generalised epilepsy. Seizure. 2019;67:11\u20134.","journal-title":"Seizure."},{"key":"4337_CR84","doi-asserted-by":"publisher","first-page":"9463","DOI":"10.1523\/JNEUROSCI.2286-08.2008","volume":"28","author":"R Bull","year":"2008","unstructured":"Bull R, Finkelstein JP, Galvez J, Sanchez G, Donoso P, Behrens MI, et al. Ischemia enhances activation by Ca2+ and redox modification of ryanodine receptor channels from rat brain cortex. J Neurosci. 2008;28:9463\u201372.","journal-title":"J Neurosci"},{"key":"4337_CR85","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1016\/j.cell.2012.06.052","volume":"150","author":"X Liu","year":"2012","unstructured":"Liu X, Betzenhauser MJ, Reiken S, Meli AC, Xie W, Chen BX, et al. Role of leaky neuronal ryanodine receptors in stress-induced cognitive dysfunction. Cell. 2012;150:1055\u201367.","journal-title":"Cell."},{"key":"4337_CR86","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1007\/s00401-017-1733-7","volume":"134","author":"A Lacampagne","year":"2017","unstructured":"Lacampagne A, Liu X, Reiken S, Bussiere R, Meli AC, Lauritzen I, et al. Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer\u2019s disease-like pathologies and cognitive deficits. Acta Neuropathol. 2017;134:749\u201367.","journal-title":"Acta Neuropathol"},{"key":"4337_CR87","doi-asserted-by":"publisher","first-page":"10153","DOI":"10.1074\/jbc.M116.743070","volume":"292","author":"R Bussiere","year":"2017","unstructured":"Bussiere R, Lacampagne A, Reiken S, Liu X, Scheuerman V, Zalk R, et al. Amyloid beta production is regulated by beta2-adrenergic signaling-mediated post-translational modifications of the ryanodine receptor. J Biol Chem. 2017;292:10153\u201368.","journal-title":"J Biol Chem"},{"key":"4337_CR88","doi-asserted-by":"publisher","first-page":"e102","DOI":"10.1093\/cvr\/cvz196","volume":"115","author":"AC Meli","year":"2019","unstructured":"Meli AC. The impact of cardiovascular diseases and new gene variants in swaying Alzheimer\u2019s disease. Cardiovasc Res. 2019;115:e102\u2013e4.","journal-title":"Cardiovasc Res"},{"key":"4337_CR89","doi-asserted-by":"publisher","first-page":"11820","DOI":"10.1523\/JNEUROSCI.0875-12.2012","volume":"32","author":"B Oules","year":"2012","unstructured":"Oules B, Del Prete D, Greco B, Zhang X, Lauritzen I, Sevalle J, et al. Ryanodine receptor blockade reduces amyloid-beta load and memory impairments in Tg2576 mouse model of Alzheimer disease. J Neurosci. 2012;32:11820\u201334.","journal-title":"J Neurosci"},{"key":"4337_CR90","doi-asserted-by":"publisher","first-page":"9458","DOI":"10.1523\/JNEUROSCI.2047-09.2009","volume":"29","author":"S Chakroborty","year":"2009","unstructured":"Chakroborty S, Goussakov I, Miller MB, Stutzmann GE. Deviant ryanodine receptor-mediated calcium release resets synaptic homeostasis in presymptomatic 3xTg-AD mice. J Neurosci. 2009;29:9458\u201370.","journal-title":"J Neurosci"},{"key":"4337_CR91","doi-asserted-by":"publisher","first-page":"5180","DOI":"10.1523\/JNEUROSCI.0739-06.2006","volume":"26","author":"GE Stutzmann","year":"2006","unstructured":"Stutzmann GE, Smith I, Caccamo A, Oddo S, Laferla FM, Parker I. Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult, and aged Alzheimer\u2019s disease mice. J Neurosci. 2006;26:5180\u20139.","journal-title":"J Neurosci"},{"key":"4337_CR92","doi-asserted-by":"crossref","unstructured":"Yao J, Sun B, Institoris A, Zhan X, Guo W, Song Z, et al. Limiting RyR2 Open Time Prevents Alzheimer\u2019s Disease-Related Neuronal Hyperactivity and Memory Loss but Not \u03b2-Amyloid Accumulation. Cell Rep. 2020;32:108169.","DOI":"10.1016\/j.celrep.2020.108169"},{"key":"4337_CR93","doi-asserted-by":"publisher","first-page":"3354","DOI":"10.1038\/s41418-020-0584-2","volume":"27","author":"F Bertan","year":"2020","unstructured":"Bertan F, Wischhof L, Sosulina L, Mittag M, Dal\u00fcgge D, Fornarelli A, et al. Loss of Ryanodine Receptor 2 impairs neuronal activity-dependent remodeling of dendritic spines and triggers compensatory neuronal hyperexcitability. Cell Death Differ. 2020;27:3354\u201373.","journal-title":"Cell Death Differ"},{"key":"4337_CR94","first-page":"C179","volume":"66","author":"X Liu","year":"2015","unstructured":"Liu X, Li J, Shen Y, Hu J, He W, Zhou Q, et al. GW26-e4458 A long-term misdiagnosis of catecholaminergic polymorphic ventricular tachycardia as epilepsy caused by RyR2 mutation. J Am Coll Cardiol. 2015;66:C179.","journal-title":"J Am Coll Cardiol"},{"key":"4337_CR95","doi-asserted-by":"publisher","first-page":"e0368","DOI":"10.1097\/MD.0000000000010368","volume":"97","author":"H Duan","year":"2018","unstructured":"Duan H, Lu Y, Yan S, Qiao L, Hua Y, Li Y, et al. A delayed diagnosis of catecholaminergic polymorphic ventricular tachycardia with a mutant of RYR2 at c.7580T>G for 6 years in a 9-year-old child. Medicine. 2018;97:e0368.","journal-title":"Medicine"},{"key":"4337_CR96","doi-asserted-by":"publisher","first-page":"e000161","DOI":"10.1136\/bmjdrc-2015-000161","volume":"4","author":"WP You","year":"2016","unstructured":"You WP, Henneberg M. Type 1 diabetes prevalence increasing globally and regionally: the role of natural selection and life expectancy at birth. BMJ Open Diabetes Res Care. 2016;4:e000161.","journal-title":"BMJ Open Diabetes Res Care"},{"key":"4337_CR97","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1111\/dme.12791","volume":"32","author":"N Holman","year":"2015","unstructured":"Holman N, Young B, Gadsby R. Current prevalence of Type 1 and Type 2 diabetes in adults and children in the UK. Diabet Med. 2015;32:1119\u201320.","journal-title":"Diabet Med"},{"key":"4337_CR98","doi-asserted-by":"publisher","first-page":"e58655","DOI":"10.1371\/journal.pone.0058655","volume":"8","author":"SS Dixit","year":"2013","unstructured":"Dixit SS, Wang T, Manzano EJ, Yoo S, Lee J, Chiang DY, et al. Effects of CaMKII-mediated phosphorylation of ryanodine receptor type 2 on islet calcium handling, insulin secretion, and glucose tolerance. PLoS One. 2013;8:e58655.","journal-title":"PLoS One"},{"key":"4337_CR99","doi-asserted-by":"publisher","first-page":"4316","DOI":"10.1172\/JCI84937","volume":"125","author":"G Santulli","year":"2015","unstructured":"Santulli G, Pagano G, Sardu C, Xie W, Reiken S, D\u2019Ascia SL, et al. Calcium release channel RyR2 regulates insulin release and glucose homeostasis. J Clin Investig. 2015;125:4316.","journal-title":"J Clin Investig"},{"key":"4337_CR100","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1074\/jbc.RA118.005683","volume":"294","author":"WR Yamamoto","year":"2019","unstructured":"Yamamoto WR, Bone RN, Sohn P, Syed F, Reissaus CA, Mosley AL, et al. Endoplasmic reticulum stress alters ryanodine receptor function in the murine pancreatic beta cell. J Biol Chem. 2019;294:168\u201381.","journal-title":"J Biol Chem"},{"key":"4337_CR101","doi-asserted-by":"publisher","first-page":"422","DOI":"10.2337\/db07-1762","volume":"58","author":"DS Luciani","year":"2009","unstructured":"Luciani DS, Gwiazda KS, Yang T-LB, Kalynyak TB, Bychkivska Y, Frey MHZ, et al. Roles of IP3R and RyR Ca2+ channels in endoplasmic reticulum stress and beta-cell death. Diabetes. 2009;58:422\u201332.","journal-title":"Diabetes."},{"key":"4337_CR102","doi-asserted-by":"publisher","first-page":"3082","DOI":"10.2337\/diabetes.54.11.3082","volume":"54","author":"N Yaras","year":"2005","unstructured":"Yaras N, Ugur M, Ozdemir S, Gurdal H, Purali N, Lacampagne A, et al. Effects of diabetes on ryanodine receptor Ca release channel (RyR2) and Ca2+ homeostasis in rat heart. Diabetes. 2005;54:3082\u20138.","journal-title":"Diabetes."},{"key":"4337_CR103","doi-asserted-by":"publisher","first-page":"1759","DOI":"10.15252\/embj.201591058","volume":"34","author":"HA Russ","year":"2015","unstructured":"Russ HA, Parent AV, Ringler JJ, Hennings TG, Nair GG, Shveygert M, et al. Controlled induction of human pancreatic progenitors produces functional beta-like cells in vitro. EMBO J. 2015;34:1759\u201372.","journal-title":"EMBO J"},{"key":"4337_CR104","doi-asserted-by":"publisher","first-page":"22","DOI":"10.2741\/2046","volume":"12","author":"J Tamargo","year":"2007","unstructured":"Tamargo J, Caballero R, Nunez L, Gomez R, Vaquero M, Delpon E. Genetically engineered mice as a model for studying cardiac arrhythmias. Front Biosci. 2007;12:22\u201338.","journal-title":"Front Biosci"},{"key":"4337_CR105","doi-asserted-by":"publisher","first-page":"3507","DOI":"10.1073\/pnas.1222878110","volume":"110","author":"J Seok","year":"2013","unstructured":"Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci USA. 2013;110:3507\u201312.","journal-title":"Proc Natl Acad Sci USA"},{"key":"4337_CR106","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","volume":"131","author":"K Takahashi","year":"2007","unstructured":"Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861\u201372.","journal-title":"Cell."},{"key":"4337_CR107","doi-asserted-by":"publisher","first-page":"e70573","DOI":"10.1371\/journal.pone.0070573","volume":"8","author":"Y Xue","year":"2013","unstructured":"Xue Y, Cai X, Wang L, Liao B, Zhang H, Shan Y, et al. Generating a non-integrating human induced pluripotent stem cell bank from urine-derived cells. PLoS One. 2013;8:e70573.","journal-title":"PLoS One"},{"key":"4337_CR108","doi-asserted-by":"publisher","first-page":"60","DOI":"10.18632\/aging.100428","volume":"4","author":"S Ohmine","year":"2012","unstructured":"Ohmine S, Squillace KA, Hartjes KA, Deeds MC, Armstrong AS, Thatava T, et al. Reprogrammed keratinocytes from elderly type 2 diabetes patients suppress senescence genes to acquire induced pluripotency. Aging. 2012;4:60\u201373.","journal-title":"Aging"},{"key":"4337_CR109","doi-asserted-by":"publisher","first-page":"2618","DOI":"10.1093\/eurheartj\/ehs203","volume":"34","author":"K Streckfuss-Bomeke","year":"2013","unstructured":"Streckfuss-Bomeke K, Wolf F, Azizian A, Stauske M, Tiburcy M, Wagner S, et al. Comparative study of human-induced pluripotent stem cells derived from bone marrow cells, hair keratinocytes, and skin fibroblasts. Eur Heart J. 2013;34:2618\u201329.","journal-title":"Eur Heart J"},{"key":"4337_CR110","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1038\/nprot.2009.241","volume":"5","author":"T Aasen","year":"2010","unstructured":"Aasen T, Izpisua Belmonte JC. Isolation and cultivation of human keratinocytes from skin or plucked hair for the generation of induced pluripotent stem cells. Nat Protoc. 2010;5:371\u201382.","journal-title":"Nat Protoc"},{"key":"4337_CR111","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/j.stem.2016.06.019","volume":"19","author":"M Nishizawa","year":"2016","unstructured":"Nishizawa M, Chonabayashi K, Nomura M, Tanaka A, Nakamura M, Inagaki A, et al. Epigenetic variation between human induced pluripotent stem cell lines is an indicator of differentiation capacity. Cell Stem Cell. 2016;19:341\u201354.","journal-title":"Cell Stem Cell"},{"key":"4337_CR112","doi-asserted-by":"crossref","unstructured":"Pesl M, Acimovic I, Pribyl J, Hezova R, Vilotic A, Fauconnier J, et al. Forced aggregation and defined factors allow highly uniform-sized embryoid bodies and functional cardiomyocytes from human embryonic and induced pluripotent stem cells. Heart Vessels. 2013;29:834\u201346.","DOI":"10.1007\/s00380-013-0436-9"},{"key":"4337_CR113","doi-asserted-by":"crossref","unstructured":"Polonen RP, Swan H, Aalto-Setala K. Mutation-specific differences in arrhythmias and drug responses in CPVT patients: simultaneous patch clamp and video imaging of iPSC derived cardiomyocytes. Mol Biol Rep. 2019;47:1067\u201377.","DOI":"10.1007\/s11033-019-05201-y"},{"key":"4337_CR114","doi-asserted-by":"crossref","unstructured":"Maizels L, Huber I, Arbel G, Tijsen AJ, Gepstein A, Khoury A, et al. Patient-Specific Drug Screening Using a Human Induced Pluripotent Stem Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Type 2. Circ Arrhythm Electrophysiol. 2017;10:e004725.","DOI":"10.1161\/CIRCEP.116.004725"},{"key":"4337_CR115","doi-asserted-by":"publisher","first-page":"80","DOI":"10.3389\/fphys.2018.00080","volume":"9","author":"JT Koivumaki","year":"2018","unstructured":"Koivumaki JT, Naumenko N, Tuomainen T, Takalo J, Oksanen M, Puttonen KA, et al. Structural immaturity of human iPSC-derived cardiomyocytes: in silico investigation of effects on function and disease modeling. Front Physiol. 2018;9:80.","journal-title":"Front Physiol"},{"key":"4337_CR116","doi-asserted-by":"publisher","first-page":"33","DOI":"10.4252\/wjsc.v11.i1.33","volume":"11","author":"P Machiraju","year":"2019","unstructured":"Machiraju P, Greenway SC. Current methods for the maturation of induced pluripotent stem cell-derived cardiomyocytes. World J stem cells. 2019;11:33\u201343.","journal-title":"World J stem cells"},{"key":"4337_CR117","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1038\/nmeth.2524","volume":"10","author":"SS Nunes","year":"2013","unstructured":"Nunes SS, Miklas JW, Liu J, Aschar-Sobbi R, Xiao Y, Zhang B, et al. Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes. Nat Methods. 2013;10:781\u20137.","journal-title":"Nat Methods"},{"key":"4337_CR118","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1073\/pnas.0906504107","volume":"107","author":"DH Kim","year":"2010","unstructured":"Kim DH, Lipke EA, Kim P, Cheong R, Thompson S, Delannoy M, et al. Nanoscale cues regulate the structure and function of macroscopic cardiac tissue constructs. Proc Natl Acad Sci USA. 2010;107:565\u201370.","journal-title":"Proc Natl Acad Sci USA"},{"key":"4337_CR119","doi-asserted-by":"publisher","first-page":"1557","DOI":"10.1161\/CIRCULATIONAHA.114.014998","volume":"134","author":"J-L Ruan","year":"2016","unstructured":"Ruan J-L, Tulloch NL, Razumova MV, Saiget M, Muskheli V, Pabon L, et al. Mechanical stress conditioning and electrical stimulation promote contractility and force maturation of induced pluripotent stem cell-derived human cardiac tissue. Circulation. 2016;134:1557\u201367.","journal-title":"Circulation."},{"key":"4337_CR120","doi-asserted-by":"publisher","first-page":"2781","DOI":"10.1038\/s41596-019-0189-8","volume":"14","author":"K Ronaldson-Bouchard","year":"2019","unstructured":"Ronaldson-Bouchard K, Yeager K, Teles D, Chen T, Ma S, Song L, et al. Engineering of human cardiac muscle electromechanically matured to an adult-like phenotype. Nat Protoc. 2019;14:2781\u2013817.","journal-title":"Nat Protoc"},{"key":"4337_CR121","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1038\/s41586-018-0016-3","volume":"556","author":"K Ronaldson-Bouchard","year":"2018","unstructured":"Ronaldson-Bouchard K, Ma SP, Yeager K, Chen T, Song L, Sirabella D, et al. Advanced maturation of human cardiac tissue grown from pluripotent stem cells. Nature. 2018;556:239\u201343.","journal-title":"Nature."},{"key":"4337_CR122","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1016\/j.cell.2018.11.042","volume":"176","author":"Y Zhao","year":"2019","unstructured":"Zhao Y, Rafatian N, Feric NT, Cox BJ, Aschar-Sobbi R, Wang EY, et al. A Platform for Generation of Chamber-Specific Cardiac Tissues and Disease Modeling. Cell. 2019;176:913\u201327 e18.","journal-title":"Cell."},{"key":"4337_CR123","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.addr.2015.04.019","volume":"96","author":"NT Feric","year":"2016","unstructured":"Feric NT, Radisic M. Maturing human pluripotent stem cell-derived cardiomyocytes in human engineered cardiac tissues. Adv Drug Deliv Rev. 2016;96:110\u201334.","journal-title":"Adv Drug Deliv Rev"},{"key":"4337_CR124","doi-asserted-by":"publisher","first-page":"H1353","DOI":"10.1152\/ajpheart.00705.2013","volume":"306","author":"A Stoehr","year":"2014","unstructured":"Stoehr A, Neuber C, Baldauf C, Vollert I, Friedrich FW, Flenner F, et al. Automated analysis of contractile force and Ca2+ transients in engineered heart tissue. Am J Physiol Heart Circulatory Physiol. 2014;306:H1353\u2013H63.","journal-title":"Am J Physiol Heart Circulatory Physiol"},{"key":"4337_CR125","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1161\/CIRCRESAHA.115.307580","volume":"117","author":"TK Feaster","year":"2015","unstructured":"Feaster TK, Cadar AG, Wang L, Williams CH, Chun YW, Hempel JE, et al. Matrigel mattress: a method for the generation of single contracting human-induced pluripotent stem cell-derived cardiomyocytes. Circ Res. 2015;117:995\u20131000.","journal-title":"Circ Res"},{"key":"4337_CR126","doi-asserted-by":"publisher","first-page":"2681","DOI":"10.1016\/j.ymthe.2018.08.012","volume":"26","author":"S Yoshida","year":"2018","unstructured":"Yoshida S, Miyagawa S, Fukushima S, Kawamura T, Kashiyama N, Ohashi F, et al. Maturation of human induced pluripotent stem cell-derived cardiomyocytes by soluble factors from human mesenchymal stem cells. Mol Ther. 2018;26:2681\u201395.","journal-title":"Mol Ther"},{"key":"4337_CR127","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.biomaterials.2015.01.067","volume":"51","author":"MC Ribeiro","year":"2015","unstructured":"Ribeiro MC, Tertoolen LG, Guadix JA, Bellin M, Kosmidis G, D\u2019Aniello C, et al. Functional maturation of human pluripotent stem cell derived cardiomyocytes in vitro-correlation between contraction force and electrophysiology. Biomaterials. 2015;51:138\u201350.","journal-title":"Biomaterials."},{"key":"4337_CR128","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1161\/CIRCRESAHA.117.311920","volume":"121","author":"SS Parikh","year":"2017","unstructured":"Parikh SS, Blackwell DJ, Gomez-Hurtado N, Frisk M, Wang L, Kim K, et al. Thyroid and glucocorticoid hormones promote functional T-tubule development in human-induced pluripotent stem cell-derived cardiomyocytes. Circ Res. 2017;121:1323\u201330.","journal-title":"Circ Res"},{"key":"4337_CR129","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1253\/circj.CJ-12-0987","volume":"77","author":"T Kamakura","year":"2013","unstructured":"Kamakura T, Makiyama T, Sasaki K, Yoshida Y, Wuriyanghai Y, Chen J, et al. Ultrastructural maturation of human-induced pluripotent stem cell-derived cardiomyocytes in a long-term culture. Circ J. 2013;77:1307\u201314.","journal-title":"Circ J"},{"key":"4337_CR130","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.7150\/thno.19390","volume":"7","author":"VJ Bhute","year":"2017","unstructured":"Bhute VJ, Bao X, Dunn KK, Knutson KR, McCurry EC, Jin G, et al. Metabolomics identifies metabolic markers of maturation in human pluripotent stem cell-derived cardiomyocytes. Theranostics. 2017;7:2078\u201391.","journal-title":"Theranostics."},{"key":"4337_CR131","doi-asserted-by":"crossref","unstructured":"Souidi M, Sleiman Y, Acimovic I, Pribyl J, Charrabi A, Baecker V, et al. Oxygen Is an Ambivalent Factor for the Differentiation of Human Pluripotent Stem Cells in Cardiac 2D Monolayer and 3D Cardiac Spheroids. Int J Mol Sci. 2021;22:662.","DOI":"10.3390\/ijms22020662"},{"key":"4337_CR132","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1159\/000335753","volume":"28","author":"A Fatima","year":"2011","unstructured":"Fatima A, Xu G, Shao K, Papadopoulos S, Lehmann M, Arnaiz-Cot JJ, et al. In vitro Modeling of Ryanodine Receptor 2 Dysfunction Using Human Induced Pluripotent Stem Cells. Cell Physiol Biochem. 2011;28:579\u201392.","journal-title":"Cell Physiol Biochem"},{"key":"4337_CR133","doi-asserted-by":"publisher","first-page":"990","DOI":"10.1016\/j.jacc.2012.02.066","volume":"60","author":"I Itzhaki","year":"2012","unstructured":"Itzhaki I, Maizels L, Huber I, Gepstein A, Arbel G, Caspi O, et al. Modeling of catecholaminergic polymorphic ventricular tachycardia with patient-specific human-induced pluripotent stem cells. J Am Coll Cardiol. 2012;60:990\u20131000.","journal-title":"J Am Coll Cardiol"},{"key":"4337_CR134","doi-asserted-by":"publisher","first-page":"e44660","DOI":"10.1371\/journal.pone.0044660","volume":"7","author":"K Kujala","year":"2012","unstructured":"Kujala K, Paavola J, Lahti A, Larsson K, Pekkanen-Mattila M, Viitasalo M, et al. Cell model of catecholaminergic polymorphic ventricular tachycardia reveals early and delayed afterdepolarizations. PLoS One. 2012;7:e44660.","journal-title":"PLoS One"},{"key":"4337_CR135","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2013.369","volume":"4","author":"E Di Pasquale","year":"2013","unstructured":"Di Pasquale E, Lodola F, Miragoli M, Denegri M, Avelino-Cruz JE, Buonocore M, et al. CaMKII inhibition rectifies arrhythmic phenotype in a patient-specific model of catecholaminergic polymorphic ventricular tachycardia. Cell Death Dis. 2013;4:e843.","journal-title":"Cell Death Dis"},{"key":"4337_CR136","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1161\/CIRCULATIONAHA.119.039711","volume":"140","author":"S-J Park","year":"2019","unstructured":"Park S-J, Zhang D, Qi Y, Li Y, Lee Keel Y, Bezzerides, Vassilios J, et al. Insights into the pathogenesis of catecholaminergic polymorphic ventricular tachycardia from engineered human heart tissue. Circulation 2019;140:390\u2013404.","journal-title":"Circulation"},{"key":"4337_CR137","doi-asserted-by":"crossref","unstructured":"Acimovic I, Refaat MM, Moreau A, Salykin A, Reiken S, Sleiman Y, et al. Post-Translational Modifications and Diastolic Calcium Leak Associated to the Novel RyR2-D3638A Mutation Lead to CPVT in Patient-Specific hiPSC-Derived Cardiomyocytes. J Clin Med. 2018;7:423.","DOI":"10.3390\/jcm7110423"},{"key":"4337_CR138","doi-asserted-by":"publisher","first-page":"1390","DOI":"10.15252\/emmm.201505719","volume":"8","author":"HD Devalla","year":"2016","unstructured":"Devalla HD, Gelinas R, Aburawi EH, Beqqali A, Goyette P, Freund C, et al. TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT. EMBO Mol Med. 2016;8:1390\u2013408.","journal-title":"EMBO Mol Med"},{"key":"4337_CR139","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1016\/j.hrthm.2020.09.007","volume":"18","author":"XH Zhang","year":"2021","unstructured":"Zhang XH, Wei H, Xia Y, Morad M. Calcium signaling consequences of RyR2 mutations associated with CPVT1 introduced via CRISPR\/Cas9 gene editing in human-induced pluripotent stem cell-derived cardiomyocytes: Comparison of RyR2-R420Q, F2483I, and Q4201R. Heart Rhythm. 2021;18:250\u201360.","journal-title":"Heart Rhythm"},{"key":"4337_CR140","doi-asserted-by":"crossref","unstructured":"Sleiman Y, Souid M, Kumar R, Yang E, Jaffr\u00e9 F, Tiing Z, et al. Modeling polymorphic ventricular tachycardia at rest using patient-specific induced pluripotent stem cell-derived cardiomyocytes. EBioMedicine. 2020;60:103024.","DOI":"10.1016\/j.ebiom.2020.103024"}],"updated-by":[{"DOI":"10.1038\/s41419-022-05468-3","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T00:00:00Z","timestamp":1669766400000}}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-04337-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-04337-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-04337-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T09:27:31Z","timestamp":1669973251000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-04337-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,1]]},"references-count":140,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["4337"],"URL":"https:\/\/doi.org\/10.1038\/s41419-021-04337-9","relation":{"correction":[{"id-type":"doi","id":"10.1038\/s41419-022-05468-3","asserted-by":"object"}]},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,1]]},"assertion":[{"value":"12 July 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 October 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 October 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 November 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1041"}}