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

Felix Beuschlein, Sheerazed Boulkroun, Andrea Osswald, Thomas Wieland, Hang N Nielsen, Urs D Lichtenauer, David Penton, Vivien R Schack, Laurence Amar, Evelyn Fischer, Anett Walther, Philipp Tauber, Thomas Schwarzmayr, Susanne Diener, Elisabeth Graf, Bruno Allolio, Benoit Samson-Couterie, Arndt Benecke, Marcus Quinkler, Francesco FalloPierre-Francois Plouin, Franco Mantero, Thomas Meitinger, Paolo Mulatero, Xavier Jeunemaitre, Richard Warth, Bente Vilsen, Maria-Christina Zennaro, Tim M Strom, Martin Reincke

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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 Ca2+ 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.
TidsskriftNature Genetics
Sider (fra-til)440–444
Antal sider5
StatusUdgivet - 17 feb. 2013


  • Conn's syndrom
  • Na,K-ATPase


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