{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T02:02:44Z","timestamp":1783130564049,"version":"3.54.6"},"reference-count":21,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2021,10,18]],"date-time":"2021-10-18T00:00:00Z","timestamp":1634515200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100009619","name":"AMED","doi-asserted-by":"publisher","award":["JP18ek0109202"],"award-info":[{"award-number":["JP18ek0109202"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Basis for Supporting Innovative Drug Discovery and Life Science Research","award":["JP20am0101080"],"award-info":[{"award-number":["JP20am0101080"]}]},{"name":"Health Science Research Grant from the Ministry of Health, Labour and Welfare of Japan for Clinical Research on Measures for Intractable Diseases","award":["H27-032"],"award-info":[{"award-number":["H27-032"]}]},{"name":"Scientific Research from the Japan Society for the Promotion of Science","award":["15K09689"],"award-info":[{"award-number":["15K09689"]}]},{"name":"Scientific Research from the Japan Society for the Promotion of Science","award":["15H04818"],"award-info":[{"award-number":["15H04818"]}]},{"name":"Scientific Research from the Japan Society for the Promotion of Science","award":["15K08243"],"award-info":[{"award-number":["15K08243"]}]},{"name":"Scientific Research from the Japan Society for the Promotion of Science","award":["19K07105"],"award-info":[{"award-number":["19K07105"]}]},{"name":"Scientific Research from the Japan Society for the Promotion of Science","award":["19H03404"],"award-info":[{"award-number":["19H03404"]}]},{"name":"Intramural Research Grant for Neurological and Psychiatric Disorders of National Center of Neurology and Psychiatry","award":["29-4"],"award-info":[{"award-number":["29-4"]}]},{"name":"Intramural Research Grant for Neurological and Psychiatric Disorders of National Center of Neurology and Psychiatry","award":["2-5"],"award-info":[{"award-number":["2-5"]}]},{"DOI":"10.13039\/100009665","name":"Vehicle Racing Commemorative Foundation","doi-asserted-by":"publisher","award":["6114"],"award-info":[{"award-number":["6114"]}],"id":[{"id":"10.13039\/100009665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,3,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Gain-of-function mutations in RYR2, encoding the cardiac ryanodine receptor channel (RyR2), cause catecholaminergic polymorphic ventricular tachycardia (CPVT). Whereas, genotype\u2013phenotype correlations of loss-of-function mutations remains unknown, due to a small number of analysed mutations. In this study, we aimed to investigate their genotype\u2013phenotype correlations in patients with loss-of-function RYR2 mutations.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>We performed targeted gene sequencing for 710 probands younger than 16-year-old with inherited primary arrhythmia syndromes (IPAS). RYR2 mutations were identified in 63 probands, and 3 probands displayed clinical features different from CPVT. A proband with p.E4146D developed ventricular fibrillation (VF) and QT prolongation whereas that with p.S4168P showed QT prolongation and bradycardia. Another proband with p.S4938F showed short-coupled variant of torsade de pointes (scTdP). To evaluate the functional alterations in these three mutant RyR2s and p.K4594Q previously reported in a long QT syndrome (LQTS), we measured Ca2+ signals in HEK293 cells and HL-1 cardiomyocytes as well as Ca2+-dependent [3H]ryanodine binding. All mutant RyR2s demonstrated a reduced Ca2+ release, an increased endoplasmic reticulum Ca2+, and a reduced [3H]ryanodine binding, indicating loss-of-functions. In HL-1 cells, the exogenous expression of S4168P and K4594Q reduced amplitude of Ca2+ transients without inducing Ca2+ waves, whereas that of E4146D and S4938F evoked frequent localized Ca2+ waves.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Loss-of-function RYR2 mutations may be implicated in various types of arrhythmias including LQTS, VF, and scTdP, depending on alteration of the channel activity. Search of RYR2 mutations in IPAS patients clinically different from CPVT will be a useful strategy to effectively discover loss-of-function RYR2 mutations.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/europace\/euab250","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T11:53:17Z","timestamp":1632225197000},"page":"497-510","source":"Crossref","is-referenced-by-count":35,"title":["Loss-of-function mutations in cardiac ryanodine receptor channel cause various types of arrhythmias including long QT syndrome"],"prefix":"10.1093","volume":"24","author":[{"given":"Sayako","family":"Hirose","sequence":"first","affiliation":[{"name":"Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shinmachi, Suita, Osaka 564-8565, Japan"},{"name":"Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Murayama","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoyuki","family":"Tetsuo","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minako","family":"Hoshiai","sequence":"additional","affiliation":[{"name":"Pediatric Heart Center, Department of Pediatrics, Yamanashi Prefectural Central Hospital, Kofu, Japan"},{"name":"Department of Pediatrics, University of Yamanashi, Chuo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Kise","sequence":"additional","affiliation":[{"name":"Pediatric Heart Disease and Adult Congenital Heart Disease Center, Showa University Hospital, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masao","family":"Yoshinaga","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, National Hospital Organization Kagoshima Medical Center, Kagoshima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisaaki","family":"Aoki","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, Osaka Women\u2019s and Children\u2019s Hospital, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megumi","family":"Fukuyama","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimin","family":"Wuriyanghai","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan"},{"name":"Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8533-8040","authenticated-orcid":false,"given":"Yuko","family":"Wada","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6125-0789","authenticated-orcid":false,"given":"Koichi","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeru","family":"Makiyama","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Kimura","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Sakurai","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9029-2339","authenticated-orcid":false,"given":"Minoru","family":"Horie","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagomi","family":"Kurebayashi","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1209-8896","authenticated-orcid":false,"given":"Seiko","family":"Ohno","sequence":"additional","affiliation":[{"name":"Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shinmachi, Suita, Osaka 564-8565, Japan"},{"name":"Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,10,18]]},"reference":[{"key":"2022030308001107200_euab250-B1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1146\/annurev.physiol.70.113006.100455","article-title":"Calcium cycling and signaling in cardiac myocytes","volume":"70","author":"Bers","year":"2008","journal-title":"Annu Rev Physiol"},{"key":"2022030308001107200_euab250-B2","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1161\/CIRCEP.114.002217","article-title":"Catecholaminergic polymorphic ventricular tachycardia in children: analysis of therapeutic strategies and outcomes from an international multicenter registry","volume":"8","author":"Roston","year":"2015","journal-title":"Circ Arrhythm Electrophysiol"},{"key":"2022030308001107200_euab250-B3","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1161\/01.RES.0000192146.85173.4b","article-title":"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","volume":"97","author":"Jiang","year":"2005","journal-title":"Circ Res"},{"key":"2022030308001107200_euab250-B4","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1161\/01.RES.0000235869.50747.e1","article-title":"Arrhythmogenesis in catecholaminergic polymorphic ventricular tachycardia: insights from a RyR2 R4496C knock-in mouse model","volume":"99","author":"Liu","year":"2006","journal-title":"Circ Res"},{"key":"2022030308001107200_euab250-B5","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1161\/01.CIR.103.2.196","article-title":"Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia","volume":"103","author":"Priori","year":"2001","journal-title":"Circulation"},{"key":"2022030308001107200_euab250-B6","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1085\/jgp.201611624","article-title":"Extensive Ca2+ leak through K4750Q cardiac ryanodine receptors caused by cytosolic and luminal Ca2+ hypersensitivity","volume":"149","author":"Uehara","year":"2017","journal-title":"J Gen Physiol"},{"key":"2022030308001107200_euab250-B7","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.joa.2015.09.008","article-title":"Current topics in catecholaminergic polymorphic ventricular tachycardia","volume":"32","author":"Sumitomo","year":"2016","journal-title":"J Arrhythm"},{"key":"2022030308001107200_euab250-B8","doi-asserted-by":"crossref","first-page":"18309","DOI":"10.1073\/pnas.0706573104","article-title":"Loss of luminal Ca2+ activation in the cardiac ryanodine receptor is associated with ventricular fibrillation and sudden death","volume":"104","author":"Jiang","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022030308001107200_euab250-B9","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.jelectrocard.2016.09.006","article-title":"A novel RYR2 loss-of-function mutation (I4855M) is associated with left ventricular non-compaction and atypical catecholaminergic polymorphic ventricular tachycardia","volume":"50","author":"Roston","year":"2017","journal-title":"J Electrocardiol"},{"key":"2022030308001107200_euab250-B10","doi-asserted-by":"crossref","first-page":"E1669","DOI":"10.1073\/pnas.1419795112","article-title":"Arrhythmogenesis in a catecholaminergic polymorphic ventricular tachycardia mutation that depresses ryanodine receptor function","volume":"112","author":"Zhao","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022030308001107200_euab250-B11","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.hrthm.2016.10.015","article-title":"A type 2 ryanodine receptor variant associated with reduced Ca(2+) release and short-coupled torsades de pointes ventricular arrhythmia","volume":"14","author":"Fujii","year":"2017","journal-title":"Heart Rhythm"},{"key":"2022030308001107200_euab250-B12","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.hrthm.2007.02.026","article-title":"A mechanism for sudden infant death syndrome (SIDS): stress-induced leak via ryanodine receptors","volume":"4","author":"Tester","year":"2007","journal-title":"Heart Rhythm"},{"key":"2022030308001107200_euab250-B13","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s00380-016-0869-z","article-title":"Prominent QTc prolongation in a patient with a rare variant in the cardiac ryanodine receptor gene","volume":"32","author":"Taniguchi","year":"2017","journal-title":"Heart Vessels"},{"key":"2022030308001107200_euab250-B14","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1253\/circj.CJ-19-0720","article-title":"Co-phenotype of left ventricular non-compaction cardiomyopathy and atypical catecholaminergic polymorphic ventricular tachycardia in association with R169Q, a ryanodine receptor type 2 missense mutation","volume":"84","author":"Nozaki","year":"2020","journal-title":"Circ J"},{"key":"2022030308001107200_euab250-B15","doi-asserted-by":"crossref","first-page":"e0130606","DOI":"10.1371\/journal.pone.0130606","article-title":"Divergent activity profiles of type 1 ryanodine receptor channels carrying malignant hyperthermia and central core disease mutations in the amino-terminal region","volume":"10","author":"Murayama","year":"2015","journal-title":"PLoS One"},{"key":"2022030308001107200_euab250-B16","doi-asserted-by":"crossref","first-page":"4153","DOI":"10.1038\/ncomms5153","article-title":"Imaging intraorganellar Ca2+ at subcellular resolution using CEPIA","volume":"5","author":"Suzuki","year":"2014","journal-title":"Nat Commun"},{"key":"2022030308001107200_euab250-B17","doi-asserted-by":"crossref","first-page":"2979","DOI":"10.1073\/pnas.95.6.2979","article-title":"HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte","volume":"95","author":"Claycomb","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022030308001107200_euab250-B18","doi-asserted-by":"crossref","first-page":"e0130329","DOI":"10.1371\/journal.pone.0130329","article-title":"Exome analyses of long QT syndrome reveal candidate pathogenic mutations in calmodulin-interacting genes","volume":"10","author":"Shigemizu","year":"2015","journal-title":"PLoS One"},{"key":"2022030308001107200_euab250-B19","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s00431-015-2689-z","article-title":"Evaluation and management of bradycardia in neonates and children","volume":"175","author":"Baruteau","year":"2016","journal-title":"Eur J Pediatr"},{"key":"2022030308001107200_euab250-B20","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1161\/CIRCRESAHA.120.316819","article-title":"RYR2 channel inhibition is the principal mechanism of flecainide action in CPVT","volume":"128","author":"Kryshtal","year":"2021","journal-title":"Circ Res"},{"key":"2022030308001107200_euab250-B21","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1016\/j.bpj.2013.08.024","article-title":"Mechanisms of beat-to-beat regulation of cardiac pacemaker cell function by Ca(2)(+) cycling dynamics","volume":"105","author":"Yaniv","year":"2013","journal-title":"Biophys J"}],"container-title":["EP Europace"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/europace\/article-pdf\/24\/3\/497\/42684497\/euab250.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/europace\/article-pdf\/24\/3\/497\/42684497\/euab250.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T08:18:52Z","timestamp":1646295532000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/europace\/article\/24\/3\/497\/6400032"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,18]]},"references-count":21,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,10,18]]},"published-print":{"date-parts":[[2022,3,2]]}},"URL":"https:\/\/doi.org\/10.1093\/europace\/euab250","relation":{},"ISSN":["1099-5129","1532-2092"],"issn-type":[{"value":"1099-5129","type":"print"},{"value":"1532-2092","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,3,1]]},"published":{"date-parts":[[2021,10,18]]}}}