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Beuschlein, F.* ; Boulkroun, S.* ; Osswald, A.* ; Wieland, T. ; Nielsen, H.N.* ; Lichtenauer, U.D.* ; Penton, D.* ; Schack, V.R.* ; Amar, L.* ; Fischer, E.* ; Walther, A. ; Tauber, P.* ; Schwarzmayr, T. ; Diener, S. ; Graf, E. ; Allolio, B. ; Samson-Couterie, B.* ; Benecke, A.* ; Quinkler, M.* ; Fallo, F.* ; Plouin, P.F.* ; Mantero, F.* ; Meitinger, T. ; Mulatero, P.* ; Jeunemaitre, X.* ; Warth, R.* ; Vilsen, B.* ; Zennaro, M.C.* ; Strom, T.M. ; Reincke, M.*

Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension.

Nat. Genet. 45, 440-444 (2013)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Primary aldosteronism is the most prevalent form of secondary hypertension. To explore molecular mechanisms of autonomous aldosterone secretion, we performed exome sequencing of aldosterone-producing adenomas (APAs). We identified somatic hotspot mutations in the ATP1A1 (encoding an Na(+)/K(+) ATPase α subunit) and ATP2B3 (encoding a Ca(2+) ATPase) genes in three and two of the nine APAs, respectively. These ATPases are expressed in adrenal cells and control sodium, potassium and calcium ion homeostasis. Functional in vitro studies of ATP1A1 mutants showed loss of pump activity and strongly reduced affinity for potassium. Electrophysiological ex vivo studies on primary adrenal adenoma cells provided further evidence for inappropriate depolarization of cells with ATPase alterations. In a collection of 308 APAs, we found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3. Mutation-positive cases showed male dominance, increased plasma aldosterone concentrations and lower potassium concentrations compared with mutation-negative cases. In summary, dominant somatic alterations in two members of the ATPase gene family result in autonomous aldosterone secretion.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Zona Glomerulosa ; Kcnj5 Mutations ; Pathways ; Atpase ; Pump ; Na,k-atpase ; Prevalence ; Cells ; Mice ; K+
ISSN (print) / ISBN 1061-4036
e-ISSN 1546-1718
Journal Nature Genetics
Quellenangaben Volume: 45, Issue: 4, Pages: 440-444 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place New York, NY
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)