{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,14]],"date-time":"2026-11-14T10:36:11Z","timestamp":1794652571232,"version":"4.9.1"},"reference-count":27,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Hypertension"],"published-print":{"date-parts":[[2014,1]]},"abstract":"<jats:p>\n            Aldosterone-producing adenomas (APAs) cause a sporadic form of primary aldosteronism and somatic mutations in the\n            <jats:italic>KCNJ5<\/jats:italic>\n            gene, which encodes the G-protein\u2013activated inward rectifier K\n            <jats:sup>+<\/jats:sup>\n            channel 4, GIRK4, account for \u224840% of APAs. Additional somatic APA mutations were identified recently in 2 other genes,\n            <jats:italic>ATP1A1<\/jats:italic>\n            and\n            <jats:italic>ATP2B3<\/jats:italic>\n            , encoding Na\n            <jats:sup>+<\/jats:sup>\n            \/K\n            <jats:sup>+<\/jats:sup>\n            -ATPase 1 and Ca\n            <jats:sup>2+<\/jats:sup>\n            -ATPase 3, respectively, at a combined prevalence of 6.8%. We have screened 112 APAs for mutations in known hotspots for genetic alterations associated with primary aldosteronism. Somatic mutations in\n            <jats:italic>ATP1A1<\/jats:italic>\n            ,\n            <jats:italic>ATP2B3<\/jats:italic>\n            , and\n            <jats:italic>KCNJ5<\/jats:italic>\n            were present in 6.3%, 0.9%, and 39.3% of APAs, respectively, and included 2 novel mutations (Na\n            <jats:sup>+<\/jats:sup>\n            \/K\n            <jats:sup>+<\/jats:sup>\n            -ATPase p.Gly99Arg and GIRK4 p.Trp126Arg).\n            <jats:italic>CYP11B2<\/jats:italic>\n            gene expression was higher in APAs harboring\n            <jats:italic>ATP1A1<\/jats:italic>\n            and\n            <jats:italic>ATP2B3<\/jats:italic>\n            mutations compared with those without these or\n            <jats:italic>KCNJ5<\/jats:italic>\n            mutations. Overexpression of Na\n            <jats:sup>+<\/jats:sup>\n            \/K\n            <jats:sup>+<\/jats:sup>\n            -ATPase p.Gly99Arg and GIRK4 p.Trp126Arg in HAC15 adrenal cells resulted in upregulation of\n            <jats:italic>CYP11B2<\/jats:italic>\n            gene expression and its transcriptional regulator\n            <jats:italic>NR4A2.<\/jats:italic>\n            Structural modeling of the Na\n            <jats:sup>+<\/jats:sup>\n            \/K\n            <jats:sup>+<\/jats:sup>\n            -ATPase showed that the Gly99Arg substitution most likely interferes with the gateway to the ion binding pocket. In vitro functional assays demonstrated that Gly99Arg displays severely impaired ATPase activity, a reduced apparent affinity for Na\n            <jats:sup>+<\/jats:sup>\n            activation of phosphorylation and K\n            <jats:sup>+<\/jats:sup>\n            inhibition of phosphorylation that indicate decreased Na\n            <jats:sup>+<\/jats:sup>\n            and K\n            <jats:sup>+<\/jats:sup>\n            binding, respectively. Moreover, whole cell patch-clamp studies established that overexpression of Na\n            <jats:sup>+<\/jats:sup>\n            \/K\n            <jats:sup>+<\/jats:sup>\n            -ATPase Gly99Arg causes membrane voltage depolarization. In conclusion, somatic mutations are common in APAs that result in an increase in\n            <jats:italic>CYP11B2<\/jats:italic>\n            gene expression and may account for the dysregulated aldosterone production in a subset of patients with sporadic primary aldosteronism.\n          <\/jats:p>","DOI":"10.1161\/hypertensionaha.113.01733","type":"journal-article","created":{"date-parts":[[2013,10,1]],"date-time":"2013-10-01T08:04:33Z","timestamp":1380614673000},"page":"188-195","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":156,"title":["Somatic\n            <i>ATP1A1<\/i>\n            ,\n            <i>ATP2B3<\/i>\n            , and\n            <i>KCNJ5<\/i>\n            Mutations in Aldosterone-Producing Adenomas"],"prefix":"10.1161","volume":"63","author":[{"given":"Tracy Ann","family":"Williams","sequence":"first","affiliation":[{"name":"From the Division of Internal Medicine and Hypertension (T.A.W., S.M., J.B., F. Buffolo, F.V., P.M.), Division of Pathology (L.A., I.C.), and Division of Endocrinology, Diabetes, and Metabolism (B.L., M.M.), Department of Medical Sciences, University of Torino, Torino, Italy; Department of Biomedicine, Aarhus University, Aarhus, Denmark (V.R.S., B.V.); Medical Cell Biology, University of Regensburg, Regensburg, Germany (J.S., R.W.); Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Monticone","sequence":"additional","affiliation":[{"name":"From the Division of Internal Medicine and Hypertension (T.A.W., S.M., J.B., F. Buffolo, F.V., P.M.), Division of Pathology (L.A., I.C.), and Division of Endocrinology, Diabetes, and Metabolism (B.L., M.M.), Department of Medical Sciences, University of Torino, Torino, Italy; Department of Biomedicine, Aarhus University, Aarhus, Denmark (V.R.S., B.V.); Medical Cell Biology, University of Regensburg, Regensburg, Germany (J.S., R.W.); Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivien R.","family":"Schack","sequence":"additional","affiliation":[{"name":"From the Division of Internal Medicine and Hypertension (T.A.W., S.M., J.B., F. Buffolo, F.V., P.M.), Division of Pathology (L.A., I.C.), and Division of Endocrinology, Diabetes, and Metabolism (B.L., M.M.), Department of Medical Sciences, University of Torino, Torino, Italy; Department of Biomedicine, Aarhus University, Aarhus, Denmark (V.R.S., B.V.); Medical Cell Biology, University of Regensburg, Regensburg, Germany (J.S., R.W.); Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Stindl","sequence":"additional","affiliation":[{"name":"From the Division of Internal Medicine and Hypertension (T.A.W., S.M., J.B., F. Buffolo, F.V., P.M.), Division of Pathology (L.A., I.C.), and Division of Endocrinology, Diabetes, and Metabolism (B.L., M.M.), Department of Medical Sciences, University of Torino, Torino, Italy; Department of Biomedicine, Aarhus University, Aarhus, Denmark (V.R.S., B.V.); Medical Cell Biology, University of Regensburg, Regensburg, Germany (J.S., R.W.); Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacopo","family":"Burrello","sequence":"additional","affiliation":[{"name":"From the Division of Internal Medicine and Hypertension (T.A.W., S.M., J.B., F. Buffolo, F.V., P.M.), Division of Pathology (L.A., I.C.), and Division of Endocrinology, Diabetes, and Metabolism (B.L., M.M.), Department of Medical Sciences, University of Torino, Torino, Italy; Department of Biomedicine, Aarhus University, Aarhus, Denmark (V.R.S., B.V.); Medical Cell Biology, University of Regensburg, Regensburg, Germany (J.S., R.W.); Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Buffolo","sequence":"additional","affiliation":[{"name":"From the Division of Internal Medicine and Hypertension (T.A.W., S.M., J.B., F. Buffolo, F.V., P.M.), Division of Pathology (L.A., I.C.), and Division of Endocrinology, Diabetes, and Metabolism (B.L., M.M.), Department of Medical Sciences, University of Torino, Torino, Italy; Department of Biomedicine, Aarhus University, Aarhus, Denmark (V.R.S., B.V.); Medical Cell Biology, University of Regensburg, Regensburg, Germany (J.S., R.W.); Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Annaratone","sequence":"additional","affiliation":[{"name":"From the Division of Internal Medicine and Hypertension (T.A.W., S.M., J.B., F. Buffolo, F.V., P.M.), Division of Pathology (L.A., I.C.), and Division of Endocrinology, Diabetes, and Metabolism (B.L., M.M.), Department of Medical Sciences, University of Torino, Torino, Italy; Department of Biomedicine, Aarhus University, Aarhus, Denmark (V.R.S., B.V.); Medical Cell Biology, University of Regensburg, Regensburg, Germany (J.S., R.W.); Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Castellano","sequence":"additional","affiliation":[{"name":"From the Division of Internal Medicine and Hypertension (T.A.W., S.M., J.B., F. Buffolo, F.V., P.M.), Division of Pathology (L.A., I.C.), and Division of Endocrinology, Diabetes, and Metabolism (B.L., M.M.), Department of Medical Sciences, University of Torino, Torino, Italy; Department of Biomedicine, Aarhus University, Aarhus, Denmark (V.R.S., B.V.); Medical Cell Biology, University of Regensburg, Regensburg, Germany (J.S., R.W.); Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Beuschlein","sequence":"additional","affiliation":[{"name":"From the Division of Internal Medicine and Hypertension (T.A.W., S.M., J.B., F. Buffolo, F.V., P.M.), Division of Pathology (L.A., I.C.), and Division of Endocrinology, Diabetes, and Metabolism (B.L., M.M.), Department of Medical Sciences, University of Torino, Torino, Italy; Department of Biomedicine, Aarhus University, Aarhus, Denmark (V.R.S., B.V.); Medical Cell Biology, University of Regensburg, Regensburg, Germany (J.S., R.W.); Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Reincke","sequence":"additional","affiliation":[{"name":"From the Division of Internal Medicine and Hypertension (T.A.W., S.M., J.B., F. Buffolo, F.V., P.M.), Division of Pathology (L.A., I.C.), and Division of Endocrinology, Diabetes, and Metabolism (B.L., M.M.), Department of Medical Sciences, University of Torino, Torino, Italy; Department of Biomedicine, Aarhus University, Aarhus, Denmark (V.R.S., B.V.); Medical Cell Biology, University of Regensburg, Regensburg, Germany (J.S., R.W.); Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Lucatello","sequence":"additional","affiliation":[{"name":"From the Division of Internal Medicine and Hypertension (T.A.W., S.M., J.B., F. Buffolo, F.V., P.M.), Division of Pathology (L.A., I.C.), and Division of Endocrinology, Diabetes, and Metabolism (B.L., M.M.), Department of Medical Sciences, University of Torino, Torino, Italy; Department of Biomedicine, Aarhus University, Aarhus, Denmark (V.R.S., B.V.); Medical Cell Biology, University of Regensburg, Regensburg, Germany (J.S., R.W.); Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Ronconi","sequence":"additional","affiliation":[{"name":"From the Division of Internal Medicine and Hypertension (T.A.W., S.M., J.B., F. Buffolo, F.V., P.M.), Division of Pathology (L.A., I.C.), and Division of Endocrinology, Diabetes, and Metabolism (B.L., M.M.), Department of Medical Sciences, University of Torino, Torino, Italy; Department of Biomedicine, Aarhus University, Aarhus, Denmark (V.R.S., B.V.); Medical Cell Biology, University of Regensburg, Regensburg, Germany (J.S., R.W.); Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Fallo","sequence":"additional","affiliation":[{"name":"From the Division of Internal Medicine and Hypertension (T.A.W., S.M., J.B., F. Buffolo, F.V., P.M.), Division of Pathology (L.A., I.C.), and Division of Endocrinology, Diabetes, and Metabolism (B.L., M.M.), Department of Medical Sciences, University of Torino, Torino, Italy; Department of Biomedicine, Aarhus University, Aarhus, Denmark (V.R.S., B.V.); Medical Cell Biology, University of Regensburg, Regensburg, Germany (J.S., R.W.); Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giampaolo","family":"Bernini","sequence":"additional","affiliation":[{"name":"From the Division of Internal Medicine and Hypertension (T.A.W., S.M., J.B., F. Buffolo, F.V., P.M.), Division of Pathology (L.A., I.C.), and Division of Endocrinology, Diabetes, and Metabolism (B.L., M.M.), Department of Medical Sciences, University of Torino, Torino, Italy; Department of Biomedicine, Aarhus University, Aarhus, Denmark (V.R.S., B.V.); Medical Cell Biology, University of Regensburg, Regensburg, Germany (J.S., R.W.); Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Maccario","sequence":"additional","affiliation":[{"name":"From the Division of Internal Medicine and Hypertension (T.A.W., S.M., J.B., F. Buffolo, F.V., P.M.), Division of Pathology (L.A., I.C.), and Division of Endocrinology, Diabetes, and Metabolism (B.L., M.M.), Department of Medical Sciences, University of Torino, Torino, Italy; Department of Biomedicine, Aarhus University, Aarhus, Denmark (V.R.S., B.V.); Medical Cell Biology, University of Regensburg, Regensburg, Germany (J.S., R.W.); Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilberta","family":"Giacchetti","sequence":"additional","affiliation":[{"name":"From the Division of Internal Medicine and Hypertension (T.A.W., S.M., J.B., F. Buffolo, F.V., P.M.), Division of Pathology (L.A., I.C.), and Division of Endocrinology, Diabetes, and Metabolism (B.L., M.M.), Department of Medical Sciences, University of Torino, Torino, Italy; Department of Biomedicine, Aarhus University, Aarhus, Denmark (V.R.S., B.V.); Medical Cell Biology, University of Regensburg, Regensburg, Germany (J.S., R.W.); Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franco","family":"Veglio","sequence":"additional","affiliation":[{"name":"From the Division of Internal Medicine and Hypertension (T.A.W., S.M., J.B., F. Buffolo, F.V., P.M.), Division of Pathology (L.A., I.C.), and Division of Endocrinology, Diabetes, and Metabolism (B.L., M.M.), Department of Medical Sciences, University of Torino, Torino, Italy; Department of Biomedicine, Aarhus University, Aarhus, Denmark (V.R.S., B.V.); Medical Cell Biology, University of Regensburg, Regensburg, Germany (J.S., R.W.); Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Warth","sequence":"additional","affiliation":[{"name":"From the Division of Internal Medicine and Hypertension (T.A.W., S.M., J.B., F. Buffolo, F.V., P.M.), Division of Pathology (L.A., I.C.), and Division of Endocrinology, Diabetes, and Metabolism (B.L., M.M.), Department of Medical Sciences, University of Torino, Torino, Italy; Department of Biomedicine, Aarhus University, Aarhus, Denmark (V.R.S., B.V.); Medical Cell Biology, University of Regensburg, Regensburg, Germany (J.S., R.W.); Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bente","family":"Vilsen","sequence":"additional","affiliation":[{"name":"From the Division of Internal Medicine and Hypertension (T.A.W., S.M., J.B., F. Buffolo, F.V., P.M.), Division of Pathology (L.A., I.C.), and Division of Endocrinology, Diabetes, and Metabolism (B.L., M.M.), Department of Medical Sciences, University of Torino, Torino, Italy; Department of Biomedicine, Aarhus University, Aarhus, Denmark (V.R.S., B.V.); Medical Cell Biology, University of Regensburg, Regensburg, Germany (J.S., R.W.); Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Mulatero","sequence":"additional","affiliation":[{"name":"From the Division of Internal Medicine and Hypertension (T.A.W., S.M., J.B., F. Buffolo, F.V., P.M.), Division of Pathology (L.A., I.C.), and Division of Endocrinology, Diabetes, and Metabolism (B.L., M.M.), Department of Medical Sciences, University of Torino, Torino, Italy; Department of Biomedicine, Aarhus University, Aarhus, Denmark (V.R.S., B.V.); Medical Cell Biology, University of Regensburg, Regensburg, Germany (J.S., R.W.); Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2012.230"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1198785"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.186478"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-3132"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0041926"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.183996"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1097\/HJH.0b013e328356139f"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2011-1733"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/hypertensionaha.111.188532"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2013.01.018"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2550"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2007-2055"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2008-0104"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/hypertensionaha.110.150318"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/17.12.3297"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0258(19980430)17:8<857::AID-SIM777>3.0.CO;2-E"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0501201102"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1677\/JME-08-0112"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-2965"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-2885"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.71.102201.141218"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature06419"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M702259200"},{"key":"e_1_3_3_25_2","first-page":"1637","article-title":"Angiotensin-II inhibits Na+\/K+ pump in rat adrenal glomerulosa cells: possible contribution to stimulation of aldosterone production.","volume":"130","author":"Hajn\u00f3czky G","year":"1992","unstructured":"Hajn\u00f3czky G, Csord\u00e1s G, Hunyady L, Kalapos MP, Balla T, Enyedi P, Sp\u00e4t A. Angiotensin-II inhibits Na+\/K+ pump in rat adrenal glomerulosa cells: possible contribution to stimulation of aldosterone production. Endocrinology. 1992;130:1637\u20131644.","journal-title":"Endocrinology"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0026-0495(99)90133-6"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2003.10.046"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0029-1243601"}],"container-title":["Hypertension"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/HYPERTENSIONAHA.113.01733","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T09:45:51Z","timestamp":1715593551000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/HYPERTENSIONAHA.113.01733"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,1]]},"references-count":27,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2014,1]]}},"alternative-id":["10.1161\/HYPERTENSIONAHA.113.01733"],"URL":"https:\/\/doi.org\/10.1161\/hypertensionaha.113.01733","relation":{},"ISSN":["0194-911X","1524-4563"],"issn-type":[{"value":"0194-911X","type":"print"},{"value":"1524-4563","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,1]]},"assertion":[{"value":"2013-05-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-09-11","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-09-30","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}