{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T15:28:58Z","timestamp":1778858938779,"version":"3.51.4"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2021,3,16]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              The cardiac ryanodine receptor type 2 (RyR2) is a large homotetramer, located in the sarcoplasmic reticulum (SR), which releases Ca\n              <jats:sup>2+<\/jats:sup>\n              from the SR during systole. The molecular mechanism underlying Ca\n              <jats:sup>2+<\/jats:sup>\n              sensing and gating of the RyR2 channel in health and disease is only partially elucidated. Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT1) is the most prevalent syndrome caused by RyR2 mutations.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              This study involves investigation of a family with 4 cases of ventricular fibrillation and sudden death and physiological tests in HEK 293 cells and normal mode analysis (NMA) computation. We found 4 clinically affected members who were homozygous for a novel RyR2 mutation, G3118R, whereas their heterozygous relatives are asymptomatic. G3118R is located in the periphery of the protein, far from the mutation hotspot regions. HEK293 cells harboring G3118R mutation inhibited Ca\n              <jats:sup>2+<\/jats:sup>\n              release in response to increasing doses of caffeine, but decreased the termination threshold for store\u2010overload\u2010induced Ca\n              <jats:sup>2+<\/jats:sup>\n              release, thus increasing the fractional Ca\n              <jats:sup>2+<\/jats:sup>\n              release in response to increasing extracellular Ca\n              <jats:sup>2+<\/jats:sup>\n              . NMA showed that G3118 affects RyR2 tetramer in a dose\u2010dependent manner, whereas in the model of homozygous mutant RyR2, the highest entropic values are assigned to the pore and the central regions of the protein.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">RyR2 G3118R is related to ventricular fibrillation and sudden death in recessive mode of inheritance and has an effect of gain of function on the protein. Despite a peripheral location, it has an allosteric effect on the stability of central and pore regions in a dose\u2010effect manner.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.120.017128","type":"journal-article","created":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T10:17:56Z","timestamp":1615285076000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["Novel RyR2 Mutation (G3118R) Is Associated With Autosomal Recessive Ventricular Fibrillation and Sudden Death: Clinical, Functional, and Computational Analysis"],"prefix":"10.1161","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6060-0209","authenticated-orcid":false,"given":"Ayelet","family":"Shauer","sequence":"first","affiliation":[{"name":"Heart Institute Hadassah\u2010Hebrew University Medical Center Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oded","family":"Shor","sequence":"additional","affiliation":[{"name":"Heart Institute Hadassah\u2010Hebrew University Medical Center Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinhong","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology The Libin Cardiovascular Institute of AlbertaUniversity of Calgary Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5365-230X","authenticated-orcid":false,"given":"Yair","family":"Elitzur","sequence":"additional","affiliation":[{"name":"Heart Institute Hadassah\u2010Hebrew University Medical Center Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nataly","family":"Kucherenko","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology Tel Aviv University Tel Aviv Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruiwu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology The Libin Cardiovascular Institute of AlbertaUniversity of Calgary Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. 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Wayne","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology The Libin Cardiovascular Institute of AlbertaUniversity of Calgary Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8222-7695","authenticated-orcid":false,"given":"Yulia","family":"Einav","sequence":"additional","affiliation":[{"name":"Faculty of Engineering Holon Institute of Technology Holon Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Luria","sequence":"additional","affiliation":[{"name":"Heart Institute Hadassah\u2010Hebrew University Medical Center Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.226845"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.2.196"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/europace\/euw389"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(89)90358-2"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.37.25971"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0184177"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3440"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.118.1.33"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2018.08.025"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20071287"},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aah5324"},{"key":"e_1_3_1_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv343"},{"key":"e_1_3_1_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_3_1_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0402388101"},{"key":"e_1_3_1_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2009.08.022"},{"key":"e_1_3_1_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)00434-3"},{"key":"e_1_3_1_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000132472.98675.EC"},{"key":"e_1_3_1_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000192146.85173.4b"},{"key":"e_1_3_1_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.718957"},{"key":"e_1_3_1_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.209312"},{"key":"e_1_3_1_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.023259"},{"key":"e_1_3_1_23_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20130805"},{"key":"e_1_3_1_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.618827"},{"key":"e_1_3_1_25_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biophys.32.110601.142445"},{"key":"e_1_3_1_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-009-0014-6"},{"key":"e_1_3_1_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/jmr.961"},{"key":"e_1_3_1_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2010.10.007"},{"key":"e_1_3_1_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1157092"},{"key":"e_1_3_1_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2014.12.020"},{"key":"e_1_3_1_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmgm.2013.10.009"},{"key":"e_1_3_1_32_2","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0185658","article-title":"Normal mode\u2010guided transition pathway generation in proteins","volume":"12","author":"Lee BH","year":"2017","unstructured":"Lee BH, Seo S, Kim MH, Kim Y, Jo S, Choi MK, Lee H, Choi JB, Kim MK. 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