{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T04:26:37Z","timestamp":1791606397016,"version":"4.3.4"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2018,11]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Paroxysmal atrial fibrillation (AF) can be caused by gain-of-function mutations in genes, encoding the cardiac potassium channel subunits\n              <jats:italic>KCNJ2<\/jats:italic>\n              ,\n              <jats:italic>KCNE1<\/jats:italic>\n              , and\n              <jats:italic>KCNH2<\/jats:italic>\n              that mediate the repolarizing potassium currents I\n              <jats:sub>k1<\/jats:sub>\n              , I\n              <jats:sub>ks<\/jats:sub>\n              , and I\n              <jats:sub>kr<\/jats:sub>\n              , respectively.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              Linkage analysis, whole-exome sequencing, and\n              <jats:italic>Xenopus<\/jats:italic>\n              oocyte electrophysiology studies were used in this study.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Through genetic studies, we showed that autosomal dominant early-onset nocturnal paroxysmal AF is caused by p.S447R mutation in\n              <jats:italic>KCND2<\/jats:italic>\n              , encoding the pore-forming (\u03b1) subunit of the Kv4.2 cardiac potassium channel. Kv4.2, along with Kv4.3, contributes to the cardiac fast transient outward K\n              <jats:sup>+<\/jats:sup>\n              current, I\n              <jats:sub>to<\/jats:sub>\n              . I\n              <jats:sub>to<\/jats:sub>\n              underlies the early phase of repolarization in the cardiac action potential, thereby setting the initial potential of the plateau phase and governing its duration and amplitude. In\n              <jats:italic>Xenopus<\/jats:italic>\n              oocytes, the mutation increased the channel\u2019s inactivation time constant and affected its regulation: p.S447 resides in a protein kinase C (PKC) phosphorylation site, which normally allows attenuation of Kv4.2 membrane expression. The mutant Kv4.2 exhibited impaired response to PKC; hence, Kv4.2 membrane expression was augmented, enhancing potassium currents. Coexpression of mutant and wild-type channels (recapitulating heterozygosity in affected individuals) showed results similar to the mutant channel alone. Finally, in a hybrid channel composed of Kv4.3 and Kv4.2, simulating the mature endogenous heterotetrameric channel underlying I\n              <jats:sub>to<\/jats:sub>\n              , the p.S447R Kv4.2 mutation exerted a gain-of-function effect on Kv4.3.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              The mutation alters Kv4.2\u2019s kinetic properties, impairs its inhibitory regulation, and exerts gain-of-function effect on both Kv4.2 homotetramers and Kv4.2-Kv4.3 heterotetramers. These effects presumably increase the repolarizing potassium current I\n              <jats:sub>to<\/jats:sub>\n              , thereby abbreviating action potential duration, creating arrhythmogenic substrate for nocturnal AF. Interestingly, Kv4.2 expression was previously shown to demonstrate circadian variation, with peak expression at daytime in murine hearts (human nighttime), with possible relevance to the nocturnal onset of paroxysmal AF symptoms in our patients. The atrial-specific phenotype suggests that targeting Kv4.2 might be effective in the treatment of nocturnal paroxysmal AF, avoiding adverse ventricular effects.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.118.002293","type":"journal-article","created":{"date-parts":[[2019,1,7]],"date-time":"2019-01-07T16:02:34Z","timestamp":1546876954000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":32,"title":["Nocturnal Atrial Fibrillation Caused by Mutation in\n            <i>KCND2<\/i>\n            , Encoding Pore-Forming (\u03b1) Subunit of the Cardiac Kv4.2 Potassium Channel"],"prefix":"10.1161","volume":"11","author":[{"given":"Max","family":"Drabkin","sequence":"first","affiliation":[{"name":"The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. (M.D., W.M., D.H., Y.Y., O.W., Y.P., R.K., O.S.B.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noam","family":"Zilberberg","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University, Beer-Sheva, Israel (N.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sasson","family":"Menahem","sequence":"additional","affiliation":[{"name":"Department of Family Medicine, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. (S.M.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wesam","family":"Mulla","sequence":"additional","affiliation":[{"name":"The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. (M.D., W.M., D.H., Y.Y., O.W., Y.P., R.K., O.S.B.)"},{"name":"Regenerative Medicine and Stem Cell Research Center and Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. (W.M., Y.E.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Halperin","sequence":"additional","affiliation":[{"name":"The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. (M.D., W.M., D.H., Y.Y., O.W., Y.P., R.K., O.S.B.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuval","family":"Yogev","sequence":"additional","affiliation":[{"name":"The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. (M.D., W.M., D.H., Y.Y., O.W., Y.P., R.K., O.S.B.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ohad","family":"Wormser","sequence":"additional","affiliation":[{"name":"The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. (M.D., W.M., D.H., Y.Y., O.W., Y.P., R.K., O.S.B.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonatan","family":"Perez","sequence":"additional","affiliation":[{"name":"The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. (M.D., W.M., D.H., Y.Y., O.W., Y.P., R.K., O.S.B.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rotem","family":"Kadir","sequence":"additional","affiliation":[{"name":"The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. 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