{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T18:09:28Z","timestamp":1788545368979,"version":"build-2803163510"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2015,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background\u2014<\/jats:title>\n                    <jats:p>\n                      Recent genome-wide association studies have demonstrated an association between\n                      <jats:italic>MYH6<\/jats:italic>\n                      , the gene encoding \u03b1-myosin heavy chain (\u03b1-MHC), and sinus node function in the general population. Moreover, a rare\n                      <jats:italic>MYH6<\/jats:italic>\n                      variant, R721W, predisposing susceptibility to sick sinus syndrome has been identified. However, the existence of disease-causing\n                      <jats:italic>MYH6<\/jats:italic>\n                      mutations for familial sick sinus syndrome and their underlying mechanisms remain unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results\u2014<\/jats:title>\n                    <jats:p>\n                      We screened 9 genotype-negative probands with sick sinus syndrome families for mutations in\n                      <jats:italic>MYH6<\/jats:italic>\n                      and identified an in-frame 3-bp deletion predicted to delete one residue (delE933) at the highly conserved coiled-coil structure within the binding motif to myosin-binding protein C in one patient. Co-immunoprecipitation analysis revealed enhanced binding of delE933 \u03b1-MHC to myosin-binding protein C. Irregular fluorescent speckles retained in the cytoplasm with substantially disrupted sarcomere striation were observed in neonatal rat cardiomyocytes transfected with \u03b1-MHC mutants carrying delE933 or R721W. In addition to the sarcomere impairments, delE933 \u03b1-MHC exhibited electrophysiological abnormalities both in vitro and in vivo. The atrial cardiomyocyte cell line HL-1 stably expressing delE933 \u03b1-MHC showed a significantly slower conduction velocity on multielectrode array than those of wild-type \u03b1-MHC or control plasmid transfected cells. Furthermore, targeted morpholino knockdown of\n                      <jats:italic>MYH6<\/jats:italic>\n                      in zebrafish significantly reduced the heart rate, which was rescued by coexpressed wild-type human \u03b1-MHC but not by delE933 \u03b1-MHC.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\u2014<\/jats:title>\n                    <jats:p>\n                      The novel\n                      <jats:italic>MYH6<\/jats:italic>\n                      mutation delE933 causes both structural damage of the sarcomere and functional impairments on atrial action propagation. This report reinforces the relevance of\n                      <jats:italic>MYH6<\/jats:italic>\n                      for sinus node function and identifies a novel pathophysiology underlying familial sick sinus syndrome.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circep.114.002534","type":"journal-article","created":{"date-parts":[[2015,2,26]],"date-time":"2015-02-26T00:33:03Z","timestamp":1424910783000},"page":"400-408","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":32,"title":["Novel Mutation in the \u03b1-Myosin Heavy Chain Gene Is Associated With Sick Sinus Syndrome"],"prefix":"10.1161","volume":"8","author":[{"given":"Taisuke","family":"Ishikawa","sequence":"first","affiliation":[{"name":"From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanchau J.","family":"Jou","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiko","family":"Nogami","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinya","family":"Kowase","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cammon B.","family":"Arrington","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spencer M.","family":"Barnett","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel T.","family":"Harrell","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuro","family":"Arimura","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiomi","family":"Tsuji","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akinori","family":"Kimura","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomasa","family":"Makita","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (T.I., D.T.H., Y.T., N.M.); Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (T.I., T.A., A.K.); Division of Pediatric Cardiology, University of Utah, Salt Lake City (C.J.J., C.B.A., S.M.B.); Cardiovascular Division, University of Tsukuba, Tsukuba (A.N.); Department of Heart Rhythm Management, Yokohama Rosai Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200003093421006"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI18062"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0402546101"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.706887"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-009-0761-0"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000147312.02673.56"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq315"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1998.2522"},{"issue":"3","key":"e_1_3_4_10_2","first-page":"H1048","article-title":"Electrophoretic separation and quantitation of cardiac myosin heavy chain isoforms in eight mammalian species.","volume":"274","author":"Reiser PJ","year":"1998","unstructured":"Reiser PJ, Kline WO. 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