{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T06:37:35Z","timestamp":1785393455422,"version":"3.55.0"},"reference-count":29,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2014,6]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>\n              Sick sinus syndrome (SSS) is a common arrhythmia often associated with aging or organic heart diseases but may also occur in a familial form with a variable mode of inheritance. Despite the identification of causative genes, including cardiac Na channel (\n              <jats:italic>SCN5A<\/jats:italic>\n              ), the pathogenesis and molecular epidemiology of familial SSS remain undetermined primarily because of its rarity.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              We genetically screened 48 members of 15 SSS families for mutations in several candidate genes and determined the functional properties of mutant Na channels using whole-cell patch clamping. We identified 6\n              <jats:italic>SCN5A<\/jats:italic>\n              mutations including a compound heterozygous mutation. Heterologously expressed mutant Na channels showed loss-of-function properties of reduced or no Na current density in conjunction with gating modulations. Among 19 family members with\n              <jats:italic>SCN5A<\/jats:italic>\n              mutations, QT prolongation and Brugada syndrome were associated in 4 and 2 individuals, respectively. Age of onset in probands carrying\n              <jats:italic>SCN5A<\/jats:italic>\n              mutations was significantly less (mean\u00b1SE, 12.4\u00b14.6 years; n=5) than in\n              <jats:italic>SCN5A<\/jats:italic>\n              -negative probands (47.0\u00b14.6 years; n=10;\n              <jats:italic>P<\/jats:italic>\n              &lt;0.001) or nonfamilial SSS (74.3\u00b10.4 years; n=538;\n              <jats:italic>P<\/jats:italic>\n              &lt;0.001). Meta-analysis of SSS probands carrying\n              <jats:italic>SCN5A<\/jats:italic>\n              mutations (n=29) indicated profound male predominance (79.3%) resembling Brugada syndrome but with a considerably earlier age of onset (20.9\u00b13.4 years).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              The notable pathophysiological overlap between familial SSS and Na channelopathy indicates that familial SSS with\n              <jats:italic>SCN5A<\/jats:italic>\n              mutations may represent a subset of cardiac Na channelopathy with strong male predominance and early clinical manifestations.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circep.113.001340","type":"journal-article","created":{"date-parts":[[2014,4,25]],"date-time":"2014-04-25T03:42:52Z","timestamp":1398397372000},"page":"511-517","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":51,"title":["Sodium Channelopathy Underlying Familial Sick Sinus Syndrome With Early Onset and Predominantly Male Characteristics"],"prefix":"10.1161","volume":"7","author":[{"given":"Keisuke","family":"Abe","sequence":"first","affiliation":[{"name":"From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taku","family":"Machida","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naokata","family":"Sumitomo","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirokazu","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimie","family":"Ohkubo","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ichiro","family":"Watanabe","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeru","family":"Makiyama","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoki","family":"Fukae","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Kohno","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel T.","family":"Harrell","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taisuke","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiomi","family":"Tsuji","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiko","family":"Nogami","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taichi","family":"Watabe","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Oginosawa","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruhiko","family":"Abe","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Maemura","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Motomura","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomasa","family":"Makita","sequence":"additional","affiliation":[{"name":"From the Departments of Molecular Physiology (K.A., T.M., D.T.H., T.I., Y.T., N.M.), Pediatrics (H.Y., H.M.), and Cardiovascular Medicine (S.F., M.K., K.M.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Departments of Pediatrics (N.S.) and Cardiovascular Medicine (K.O., I.W.), Nihon University Graduate School of Medicine, Tokyo, Japan; Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.M.); Division of Heart Rhythm..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.29.4.469"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1968.03150030101028"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200003093421006"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200005113421902"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(94)90347-6"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa013040"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200318062"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2005.02.024"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000069689.09869.A8"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2005.06.032"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2005.08.043"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200316387"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0402546101"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.781"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.616011"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2012.11.062"},{"key":"e_1_3_4_18_2","first-page":"815","volume-title":"In: Heart Disease: A Textbook of Cardiovascular Medicine","author":"Olgin JE","year":"2001","unstructured":"Olgin JE, Zipes DP. Specific arrhythmias: diagnosis and treatment. , Braunwald E, Zipes DP, Libby P, eds. In: Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia, PA: W.B. Saunders Company; 2001:815\u2013899."},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.111.962019"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000152479.54298.51"},{"key":"e_1_3_4_21_2","first-page":"2219","article-title":"The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome.","volume":"118","author":"Makita N","year":"2008","unstructured":"Makita N, Behr E, Shimizu W, Horie M, Sunami A, Crotti L, Schulze-Bahr E, Fukuhara S, Mochizuki N, Makiyama T, Itoh H, Christiansen M, McKeown P, Miyamoto K, Kamakura S, Tsutsui H, Schwartz PJ, George AL, Roden DM. The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome. 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