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.
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NCBI Reference Sequence
Protein Data Bank
Munich and Regensburg. This work has been made possible by a grant of the Else Kröner–Fresenius-Stiftung in support of the German Conn's Registry-Else-Kröner Hyperaldosteronism Registry (to M.R.). Additional funding was received from the Deutsche Forschungsgemeinschaft to F.B. and M.R. (Re 752/17-1) and R.W. (FOR1086). The work was also supported by the German Ministry of Education and Research (01GR0802 and 01GM0867), the European Commission's Seventh Framework Programme (261123, GEUVADIS) and the DZHK.
Paris. We thank H. Lefèbvre and E. Louiset (INSERM U982 and University Hospital of Rouen) and M. Sibony (Assistance Publique–Hôpitaux de Paris, Hôpital Cochin) for providing control adrenal samples. We thank the COMETE (COrtico et MEdullo-surrénale: les Tumeurs Endocrines) network for providing tissue samples from individuals with APA. This work was funded through institutional support from INSERM and by the Agence Nationale pour la Recherche (ANR Physio 2007, 013-01; Genopat 2008, 08-GENO-021), the Fondation pour la Recherche sur l'Hypertension Artérielle (AO 2007), the Fondation pour la Recherche Médicale (ING20101221177), the Programme Hospitalier de Recherche Clinique (PHRC grant AOM 06179) and by grants from INSERM and the Ministère Délégué à la Recherche et des Nouvelles Technologies.
Aarhus. This work was supported in part by grants to B.V. from the Danish Medical Research Council, the Novo Nordisk Foundation (Fabrikant Vilhelm Pedersen og Hustrus Legat) and the Lundbeck Foundation.
Turin. This study was supported by grants from the Fondi Ricerca Ex-60% MIUR (Ministry of University, Scientific and Technological Research) 2012 and the Compagnia di San Paolo.
Supplementary Figures 1 and 2 and Supplementary Tables 1–5