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Trans. R. Soc. B"],"published-print":{"date-parts":[[2023,6,19]]},"abstract":"<jats:p>\n                    J wave syndrome (JWS) is an inherited cardiac channelopathy associated with malignant ventricular arrhythmias and sudden cardiac death (SCD), which comprises early repolarization syndrome and Brugada syndrome. Here, we explore the association between variants in the\n                    <jats:italic>L<\/jats:italic>\n                    -type calcium channel gene subunits, \u03b1\n                    <jats:sub>1C<\/jats:sub>\n                    (\n                    <jats:italic>CACNA1C<\/jats:italic>\n                    ) and \u03b22b (\n                    <jats:italic>CACNB2b<\/jats:italic>\n                    ), and the JWS phenotype. Using next-generation genetic sequencing of 402 JWS probands and their family members, we identified a\n                    <jats:italic>CACNA1C<\/jats:italic>\n                    -G37R (p.Gly37Arg) mutation in five individuals in four families, two of which had a family history of SCD as well as a\n                    <jats:italic>CACNB2b<\/jats:italic>\n                    -S143F (p.Ser143Phe) mutation in seven individuals in three families, two of which had a family history of SCD. The variants were located in exon 2 in\n                    <jats:italic>CACNA1C<\/jats:italic>\n                    and exon 5 in\n                    <jats:italic>CACNB2b<\/jats:italic>\n                    ; both were in highly conserved amino acid residues. Whole-cell patch-clamp results showed that compared with the wild-type group, calcium current density of\n                    <jats:italic>CACNB2b-<\/jats:italic>\n                    S143F and\n                    <jats:italic>CACNA1C<\/jats:italic>\n                    -G37R were significantly lower displaying a dominant-negative effect. Our findings provide further support for the hypothesis that variants in\n                    <jats:italic>CACNA1C<\/jats:italic>\n                    and\n                    <jats:italic>CACNB2b<\/jats:italic>\n                    are associated with JWS. The results suggest that mutations in these two genes lead to loss-of-function of the cardiac calcium channel current warranting their inclusion in genetic screening protocols.\n                  <\/jats:p>\n                  <jats:p>This article is part of the theme issue \u2018The heartbeat: its molecular basis and physiological mechanisms\u2019.<\/jats:p>","DOI":"10.1098\/rstb.2022.0286","type":"journal-article","created":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T02:39:17Z","timestamp":1682908757000},"update-policy":"https:\/\/doi.org\/10.1098\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Functional identification of hot-spot mutations in cardiac calcium channel genes associated with the J wave syndromes"],"prefix":"10.1098","volume":"378","author":[{"given":"Bin","family":"Zeng","sequence":"first","affiliation":[{"name":"Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China"},{"name":"Hubei Key Laboratory of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9494-6064","authenticated-orcid":true,"given":"Xiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China"},{"name":"Hubei Key Laboratory of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rainer","family":"Schimpf","sequence":"additional","affiliation":[{"name":"Cardiology Practice Clinic, Ludwig-Guttmann-Str. 11, Ludwigshafen, Ludwigshafen-Neustadt, 67071, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Powers","sequence":"additional","affiliation":[{"name":"Department of Biology, University at Albany, State University of New York, Albany, NY, 12222, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Glikson","sequence":"additional","affiliation":[{"name":"Jesselson Integrated Heart Center, Shaare Zedek Medical Center and Hebrew University Faculty of Medicine, Jerusalem, 91031, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles","family":"Antzelevitch","sequence":"additional","affiliation":[{"name":"Lankenau Institute for Medical Research, and Lankenau Heart Institute, Wynnwood, Pennsylvania, PA, 19096, USA"},{"name":"Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0994-8434","authenticated-orcid":true,"given":"Dan","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China"},{"name":"Hubei Key Laboratory of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hector","family":"Barajas-Martinez","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China"},{"name":"Hubei Key Laboratory of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People's Republic of China"},{"name":"Lankenau Institute for Medical Research, and Lankenau Heart Institute, Wynnwood, Pennsylvania, PA, 19096, USA"},{"name":"Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"175","published-online":{"date-parts":[[2023,5]]},"reference":[{"key":"e_1_3_7_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2009.12.006"},{"key":"e_1_3_7_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2006.07.010"},{"key":"e_1_3_7_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.976092"},{"key":"e_1_3_7_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000152479.54298.51"},{"key":"e_1_3_7_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv316"},{"key":"e_1_3_7_7_2","first-page":"665","article-title":"J-wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge","volume":"19","author":"Antzelevitch C","year":"2017","unstructured":"Antzelevitch C et al. 2017 J-wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge. 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