{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:26:30Z","timestamp":1791264390705,"version":"4.1.0"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2019,1]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Inherited forms of sinus node dysfunction (SND) clinically include bradycardia, sinus arrest, and chronotropic incompetence and may serve as disease models to understand sinus node physiology and impulse generation. Recently, a gain-of-function mutation in the G-protein gene\n              <jats:italic>GNB2<\/jats:italic>\n              led to enhanced activation of the GIRK (G-protein activated inwardly rectifying K\n              <jats:sup>+<\/jats:sup>\n              channel). Thus, human cardiac GIRK channels are important for heart rate regulation and subsequently, genes encoding their subunits Kir3.1 and Kir3.4 (\n              <jats:italic>KCNJ3<\/jats:italic>\n              and\n              <jats:italic>KCNJ5<\/jats:italic>\n              ) are potential candidates for inherited SND in human.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              We performed a combined approach of targeted sequencing of\n              <jats:italic>KCNJ3<\/jats:italic>\n              and\n              <jats:italic>KCNJ5<\/jats:italic>\n              in 52 patients with idiopathic SND and subsequent whole exome sequencing of additional family members in a genetically affected patient. A putative novel disease-associated gene variant was functionally analyzed by voltage-clamp experiments using various heterologous cell expression systems (Xenopus oocytes, CHO cells, and rat atrial cardiomyocytes).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              In a 3-generation family with SND we identified a novel variant in\n              <jats:italic>KCNJ5<\/jats:italic>\n              which leads to an amino acid substitution (p.Trp101Cys) in the first transmembrane domain of the Kir3.4 subunit of the cardiac GIRK channel. The identified variant cosegregated with the disease in the family and was absent in the Exome Variant Server and Exome Aggregation Consortium databases. Expression of mutant Kir3.4 (\u00b1native Kir3.1) in different heterologous cell expression systems resulted in increased GIRK currents (\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>K,ACh<\/jats:sub>\n              ) and a reduced inward rectification which was not compensated by intracellular spermidine. Moreover, in silico modeling of heterotetrameric mutant GIRK channels indicates a structurally altered binding site for spermine.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>For the first time, an inherited gain-of-function mutation in the human GIRK3.4 causes familial human SND. The increased activity of GIRK channels is likely to lead to a sustained hyperpolarization of pacemaker cells and thereby reduces heart rate. Modulation of human GIRK channels may pave a way for further treatment of cardiac pacemaking.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.118.002238","type":"journal-article","created":{"date-parts":[[2019,1,15]],"date-time":"2019-01-15T19:03:24Z","timestamp":1547579004000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":46,"title":["Familial Sinus Node Disease Caused by a Gain of GIRK (G-Protein Activated Inwardly Rectifying K\n            <sup>+<\/sup>\n            Channel) Channel Function"],"prefix":"10.1161","volume":"12","author":[{"given":"Johanna","family":"Ku\u00df","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital M\u00fcnster, Germany (J.K., B.S., S.Z., G.S., E.S.-B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Stallmeyer","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital M\u00fcnster, Germany (J.K., B.S., S.Z., G.S., E.S.-B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Goldstein","sequence":"additional","affiliation":[{"name":"Institute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, Germany (M.G., S.R., N.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Rinn\u00e9","sequence":"additional","affiliation":[{"name":"Institute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, Germany (M.G., S.R., N.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane","family":"Pees","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, University Children\u2019s Hospital Vienna, Austria (C.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Zumhagen","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital M\u00fcnster, Germany (J.K., B.S., S.Z., G.S., E.S.-B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiscard","family":"Seebohm","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital M\u00fcnster, Germany (J.K., B.S., S.Z., G.S., E.S.-B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels","family":"Decher","sequence":"additional","affiliation":[{"name":"Institute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, Germany (M.G., S.R., N.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lutz","family":"Pott","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Institute of Physiology, Ruhr-University Bochum, Germany (L.P., M.-C.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-C\u00e9cile","family":"Kienitz","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Institute of Physiology, Ruhr-University Bochum, Germany (L.P., M.-C.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Schulze-Bahr","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital M\u00fcnster, Germany (J.K., B.S., S.Z., G.S., 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