{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:32:21Z","timestamp":1791894741371,"version":"4.3.4"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"18","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2019,4,30]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Bradyarrhythmia is a common clinical manifestation. Although the majority of cases are acquired, genetic analysis of families with bradyarrhythmia has identified a growing number of causative gene mutations. Because the only ultimate treatment for symptomatic bradyarrhythmia has been invasive surgical implantation of a pacemaker, the discovery of novel therapeutic molecular targets is necessary to improve prognosis and quality of life.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>We investigated a family containing 7 individuals with autosomal dominant bradyarrhythmias of sinus node dysfunction, atrial fibrillation with slow ventricular response, and atrioventricular block. To identify the causative mutation, we conducted the family-based whole exome sequencing and genome-wide linkage analysis. We characterized the mutation-related mechanisms based on the pathophysiology in vitro. After generating a transgenic animal model to confirm the human phenotypes of bradyarrhythmia, we also evaluated the efficacy of a newly identified molecular-targeted compound to upregulate heart rate in bradyarrhythmias by using the animal model.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              We identified one heterozygous mutation,\n              <jats:italic>KCNJ3<\/jats:italic>\n              c.247A&gt;C, p.N83H, as a novel cause of hereditary bradyarrhythmias in this family.\n              <jats:italic>KCNJ3<\/jats:italic>\n              encodes the inwardly rectifying potassium channel Kir3.1, which combines with Kir3.4 (encoded by\n              <jats:italic>KCNJ5<\/jats:italic>\n              ) to form the acetylcholine-activated potassium channel (\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>KACh<\/jats:sub>\n              channel) with specific expression in the atrium. An additional study using a genome cohort of 2185 patients with sporadic atrial fibrillation revealed another 5 rare mutations in\n              <jats:italic>KCNJ3<\/jats:italic>\n              and\n              <jats:italic>KCNJ5<\/jats:italic>\n              , suggesting the relevance of both genes to these arrhythmias. Cellular electrophysiological studies revealed that the\n              <jats:italic>KCNJ3<\/jats:italic>\n              p.N83H mutation caused a gain of\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>KACh<\/jats:sub>\n              channel function by increasing the basal current, even in the absence of m\n              <jats:sub>2<\/jats:sub>\n              muscarinic receptor stimulation. We generated transgenic zebrafish expressing mutant human\n              <jats:italic>KCNJ3<\/jats:italic>\n              in the atrium specifically. It is interesting to note that the selective\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>KACh<\/jats:sub>\n              channel blocker NIP-151 repressed the increased current and improved bradyarrhythmia phenotypes in the mutant zebrafish.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              The\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>KACh<\/jats:sub>\n              channel is associated with the pathophysiology of bradyarrhythmia and atrial fibrillation, and the mutant\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>KACh<\/jats:sub>\n              channel (\n              <jats:italic>KCNJ3<\/jats:italic>\n              p.N83H) can be effectively inhibited by NIP-151, a selective\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>KACh<\/jats:sub>\n              channel blocker. Thus, the\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>KACh<\/jats:sub>\n              channel might be considered to be a suitable pharmacological target for patients who have bradyarrhythmia with a gain-of-function mutation in the\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>KACh<\/jats:sub>\n              channel.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.118.036761","type":"journal-article","created":{"date-parts":[[2019,2,15]],"date-time":"2019-02-15T10:00:47Z","timestamp":1550224847000},"page":"2157-2169","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":81,"title":["Mutant\n            <i>KCNJ3<\/i>\n            and\n            <i>KCNJ5<\/i>\n            Potassium Channels as Novel Molecular Targets in Bradyarrhythmias and Atrial Fibrillation"],"prefix":"10.1161","volume":"139","author":[{"given":"Noriaki","family":"Yamada","sequence":"first","affiliation":[{"name":"Departments of Cardiovascular Medicine (N.Y., Y.A., A.T., H. Kioka, Y.M., H.S., Y.S.), Osaka University Graduate School of Medicine, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Asano","sequence":"additional","affiliation":[{"name":"Departments of Cardiovascular Medicine (N.Y., Y.A., A.T., H. Kioka, Y.M., H.S., Y.S.), Osaka University Graduate School of Medicine, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Fujita","sequence":"additional","affiliation":[{"name":"Department of Onco-cardiology, Osaka International Cancer Institute, Japan (M.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Yamazaki","sequence":"additional","affiliation":[{"name":"Departments of Cell Biology (S.Y.), National Cerebral and Cardiovascular Center, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Inanobe","sequence":"additional","affiliation":[{"name":"Pharmacology (A.I., Y.K.), Osaka University Graduate School of Medicine, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norio","family":"Matsuura","sequence":"additional","affiliation":[{"name":"Departments of Health and Environmental Sciences (N.M.), Kyoto University Graduate School of Medicine, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hatasu","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Life and Health Sciences Chubu University, Kasugai, Japan (H. Kobayashi)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiko","family":"Ohno","sequence":"additional","affiliation":[{"name":"Bioscience and Genetics (S.O.), National Cerebral and Cardiovascular Center, Suita, Japan."},{"name":"Center for Epidemiologic Research in Asia (S.O., K.M., H.U., M.H.), Shiga University of Medical Science, Otsu, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Ebana","sequence":"additional","affiliation":[{"name":"Life Science and Bioethics Research Center (Y.E.), Tokyo Medical and Dental University, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Tsukamoto","sequence":"additional","affiliation":[{"name":"Medical Biochemistry (O.T., H. Kato, Y.N., S.T.), Osaka University Graduate School of Medicine, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saki","family":"Ishino","sequence":"additional","affiliation":[{"name":"Center of Medical Innovation and Translational Research (S.I.), Osaka University Graduate School of Medicine, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Takuwa","sequence":"additional","affiliation":[{"name":"Departments of Cardiovascular Medicine (N.Y., Y.A., A.T., H. Kioka, Y.M., H.S., Y.S.), Osaka University Graduate School of Medicine, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidetaka","family":"Kioka","sequence":"additional","affiliation":[{"name":"Departments of Cardiovascular Medicine (N.Y., Y.A., A.T., H. Kioka, Y.M., H.S., Y.S.), Osaka University Graduate School of Medicine, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Pharmaceuticals Division, Nissan Chemical Corporation, Tokyo, Japan (T.Y., N.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norio","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Pharmaceuticals Division, Nissan Chemical Corporation, Tokyo, Japan (T.Y., N.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitar P.","family":"Zankov","sequence":"additional","affiliation":[{"name":"Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology (D.P.Z., A.S., H.O.), Shiga University of Medical Science, Otsu, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akio","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology (D.P.Z., A.S., H.O.), Shiga University of Medical Science, Otsu, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Asakura","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan (M.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Asanuma","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Meiji University of Integrative Medicine, Nantan, Japan (H.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisakazu","family":"Kato","sequence":"additional","affiliation":[{"name":"Medical Biochemistry (O.T., H. Kato, Y.N., S.T.), Osaka University Graduate School of Medicine, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuya","family":"Nishida","sequence":"additional","affiliation":[{"name":"Medical Biochemistry (O.T., H. Kato, Y.N., S.T.), Osaka University Graduate School of Medicine, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Miyashita","sequence":"additional","affiliation":[{"name":"Departments of Cardiovascular Medicine (N.Y., Y.A., A.T., H. Kioka, Y.M., H.S., Y.S.), Osaka University Graduate School of Medicine, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruki","family":"Shinomiya","sequence":"additional","affiliation":[{"name":"Departments of Cardiovascular Medicine (N.Y., Y.A., A.T., H. Kioka, Y.M., H.S., Y.S.), Osaka University Graduate School of Medicine, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobu","family":"Naiki","sequence":"additional","affiliation":[{"name":"Departments of Cardiovascular Medicine (N.N., M.H.), Shiga University of Medical Science, Otsu, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenshi","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan (K.H., M.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeru","family":"Makiyama","sequence":"additional","affiliation":[{"name":"Cardiovascular Medicine (T. Makiyama), Kyoto University Graduate School of Medicine, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisakazu","family":"Ogita","sequence":"additional","affiliation":[{"name":"Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology (D.P.Z., A.S., H.O.), Shiga University of Medical Science, Otsu, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuyuki","family":"Miura","sequence":"additional","affiliation":[{"name":"Center for Epidemiologic Research in Asia (S.O., K.M., H.U., M.H.), Shiga University of Medical Science, Otsu, Japan."},{"name":"Public Health (K.M., H.U.), Shiga University of Medical Science, Otsu, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotsugu","family":"Ueshima","sequence":"additional","affiliation":[{"name":"Center for Epidemiologic Research in Asia (S.O., K.M., H.U., M.H.), Shiga University of Medical Science, Otsu, Japan."},{"name":"Public Health (K.M., H.U.), Shiga University of Medical Science, Otsu, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Issei","family":"Komuro","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine, Japan (I.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masakazu","family":"Yamagishi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan (K.H., M.Y.)."},{"name":"Department of Human Sciences, Osaka University of Human Sciences, Settsu, Japan (M.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoru","family":"Horie","sequence":"additional","affiliation":[{"name":"Center for Epidemiologic Research in Asia (S.O., K.M., H.U., M.H.), Shiga University of Medical Science, Otsu, Japan."},{"name":"Departments of Cardiovascular Medicine (N.N., M.H.), Shiga University of Medical Science, Otsu, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Kawakami","sequence":"additional","affiliation":[{"name":"Division of Molecular and Developmental Biology, National Institute of Genetics, Mishima, Japan (K.K.)."},{"name":"Department of Genetics, SOKENDAI (The Graduate University for Advanced Studies), Mishima, Japan (K.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsushi","family":"Furukawa","sequence":"additional","affiliation":[{"name":"Department of Bioinformational Pharmacology (T.F.), Tokyo Medical and Dental University, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akio","family":"Koizumi","sequence":"additional","affiliation":[{"name":"Public Interest Foundation Kyoto Hokenkai, Japan (A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihisa","family":"Kurachi","sequence":"additional","affiliation":[{"name":"Pharmacology (A.I., Y.K.), Osaka University Graduate School of Medicine, Suita, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Sakata","sequence":"additional","affiliation":[{"name":"Departments of Cardiovascular Medicine (N.Y., Y.A., A.T., H. 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