{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T23:32:40Z","timestamp":1772580760770,"version":"3.50.1"},"reference-count":30,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2016,7,12]],"date-time":"2016-07-12T00:00:00Z","timestamp":1468281600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100005187","name":"National and Kapodistrian University of Athens","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005187","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Endocrinology"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Germline mutations of the <jats:italic><jats:styled-content style=\"fixed-case\">KCNJ<\/jats:styled-content>5<\/jats:italic> gene encoding Kir3\u00b74, a member of the inwardly rectifying K<jats:sup>+<\/jats:sup> channel, have been identified in \u2018normal\u2019 adrenal glands, patients with familial hyperaldosteronism (<jats:styled-content style=\"fixed-case\">FH<\/jats:styled-content>) type <jats:styled-content style=\"fixed-case\">III<\/jats:styled-content>, aldosterone\u2010producing adenomas (<jats:styled-content style=\"fixed-case\">APA<\/jats:styled-content>s) and sporadic cases of primary aldosteronism (<jats:styled-content style=\"fixed-case\">PA<\/jats:styled-content>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To present two novel <jats:italic><jats:styled-content style=\"fixed-case\">KCNJ<\/jats:styled-content>5<\/jats:italic> gene mutations in hypertensive patients without <jats:styled-content style=\"fixed-case\">PA<\/jats:styled-content>, but with Adrenocorticotropic hormone (ACTH)\u2010dependent aldosterone hypersecretion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design and Patients<\/jats:title><jats:p>Two hypertensive patients without <jats:styled-content style=\"fixed-case\">PA<\/jats:styled-content>, who exhibited enhanced <jats:styled-content style=\"fixed-case\">ACTH<\/jats:styled-content>\u2010dependent response of aldosterone secretion, underwent genetic testing for the presence of the <jats:italic><jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>11B1\/<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>11B2<\/jats:italic> chimeric gene and <jats:italic><jats:styled-content style=\"fixed-case\">KCNJ<\/jats:styled-content>5<\/jats:italic> gene mutations. Genomic <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> was isolated from peripheral white blood cells, and the exons of the entire coding regions of the above genes were amplified and sequenced. Electrophysiological studies were performed to determine the effect of identified mutation(s) on the membrane reversal potentials. Structural biology studies were also carried out.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Two novel germline heterozygous <jats:italic><jats:styled-content style=\"fixed-case\">KCNJ<\/jats:styled-content>5<\/jats:italic> mutations, p.V259M and p.Y348N, were detected in the two subjects. Electrophysiological studies showed that the Y348N mutation resulted in significantly less negative reversal potentials, suggesting loss of ion selectivity, while the V259M mutation did not affect the Kir3.4 current. In the mutated structural biology model, the N348 mutant resulted in significant loss of the ability for hydrogen bonding, while the M259 mutant was capable of establishing weaker interactions. The <jats:italic><jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>11B1\/<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>11B2<\/jats:italic> chimeric gene was not detected.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings expand on the clinical spectrum of phenotypes associated with <jats:italic><jats:styled-content style=\"fixed-case\">KCNJ<\/jats:styled-content>5<\/jats:italic> mutations and implicate these mutations in the pathogenesis of hypertension associated with increased aldosterone response to <jats:styled-content style=\"fixed-case\">ACTH<\/jats:styled-content> stimulation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cen.13132","type":"journal-article","created":{"date-parts":[[2016,6,13]],"date-time":"2016-06-13T10:52:14Z","timestamp":1465815134000},"page":"845-851","source":"Crossref","is-referenced-by-count":18,"title":["Functional characterization of two novel germline mutations of the <i><scp>KCNJ<\/scp>5<\/i> gene in hypertensive patients without primary aldosteronism but with <scp>ACTH<\/scp>\u2010dependent aldosterone hypersecretion"],"prefix":"10.1111","volume":"85","author":[{"given":"Amalia","family":"Sertedaki","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Metabolism and Diabetes First Department of Pediatrics National and Kapodistrian University of Athens Medical School \u2018Aghia Sophia\u2019 Children's Hospital Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Athina","family":"Markou","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes Center \u2018G. 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