{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:26:31Z","timestamp":1791264391044,"version":"4.1.0"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2017,5,12]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Familial sinus node and atrioventricular conduction dysfunction is a rare disorder that leads to paroxysmal dizziness, fatigue, and syncope because of a temporarily or permanently reduced heart rate. To date, only a few genes for familial sinus and atrioventricular conduction dysfunction are known, and the majority of cases remain pathogenically unresolved.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>We aim to identify the disease gene in a large 3-generation family (n=25) with autosomal dominant sinus node dysfunction (SND) and atrioventricular block (AVB) and to characterize the mutation-related pathomechanisms in familial SND+AVB.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              Genome-wide linkage analysis mapped the SND+AVB disease locus to chromosome 7q21.1-q31.1 (2-point logarithm of the odds score: 4.64; \u03b8=0); in this region, targeted exome sequencing identified a novel heterozygous mutation (p.Arg52Leu) in the\n              <jats:italic>GNB2<\/jats:italic>\n              gene that strictly cosegregated with the SND+AVB phenotype.\n              <jats:italic>GNB2<\/jats:italic>\n              encodes the \u03b2\n              <jats:sub>2<\/jats:sub>\n              subunit (G\u03b2\n              <jats:sub>2<\/jats:sub>\n              ) of the heterotrimeric G-protein complex that is being released from G-protein\u2013coupled receptors on vagal stimulation. In 2 heterologous expression systems (HEK-293T cells and\n              <jats:italic>Xenopus laevis<\/jats:italic>\n              oocytes), an enhanced activation of the G-protein\u2013activated K\n              <jats:sup>+<\/jats:sup>\n              channel (GIRK; Kir3.1\/Kir3.4) was shown when mutant G\u03b2\n              <jats:sub>2<\/jats:sub>\n              was coexpressed with G\u03b3\n              <jats:sub>2<\/jats:sub>\n              ; this was in contrast to coexpression of mutant G\u03b2\n              <jats:sub>2<\/jats:sub>\n              -G\u03b3\n              <jats:sub>2<\/jats:sub>\n              with other cardiac ion channels (HCN4, HCN2, and Cav1.2). Molecular dynamics simulations suggested a reduced binding property of mutant G\u03b2\n              <jats:sub>2<\/jats:sub>\n              to cardiac GIRK channels when compared with native G\u03b2\n              <jats:sub>2<\/jats:sub>\n              .\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              A\n              <jats:italic>GNB2<\/jats:italic>\n              gene mutation is associated with familial SND+AVB and leads to a sustained activation of cardiac GIRK channels, which is likely to hyperpolarize the myocellular membrane potential and thus reduces their spontaneous activity. Our findings describe for the first time a role of a mutant G-protein in the nonsyndromic pacemaker disease because of GIRK channel activation.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.116.310112","type":"journal-article","created":{"date-parts":[[2017,2,21]],"date-time":"2017-02-21T01:40:24Z","timestamp":1487641224000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":52,"title":["A Mutation in the G-Protein Gene\n            <i>GNB2<\/i>\n            Causes Familial Sinus Node and Atrioventricular Conduction Dysfunction"],"prefix":"10.1161","volume":"120","author":[{"given":"Birgit","family":"Stallmeyer","sequence":"first","affiliation":[{"name":"From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children\u2019s Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Ku\u00df","sequence":"additional","affiliation":[{"name":"From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children\u2019s Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Kotthoff","sequence":"additional","affiliation":[{"name":"From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children\u2019s Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Zumhagen","sequence":"additional","affiliation":[{"name":"From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children\u2019s Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsty","family":"Vowinkel","sequence":"additional","affiliation":[{"name":"From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children\u2019s Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Rinn\u00e9","sequence":"additional","affiliation":[{"name":"From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children\u2019s Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina A.","family":"Matschke","sequence":"additional","affiliation":[{"name":"From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children\u2019s Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinna","family":"Friedrich","sequence":"additional","affiliation":[{"name":"From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children\u2019s Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Schulze-Bahr","sequence":"additional","affiliation":[{"name":"From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children\u2019s Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Rust","sequence":"additional","affiliation":[{"name":"From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children\u2019s Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiscard","family":"Seebohm","sequence":"additional","affiliation":[{"name":"From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children\u2019s Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels","family":"Decher","sequence":"additional","affiliation":[{"name":"From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children\u2019s Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Schulze-Bahr","sequence":"additional","affiliation":[{"name":"From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); 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