Abstract

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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Acknowledgements

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.

Author information

Author notes

    • Maria-Christina Zennaro
    •  & Tim M Strom

    These authors contributed equally to this work.

Affiliations

  1. Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany.

    • Felix Beuschlein
    • , Andrea Osswald
    • , Urs D Lichtenauer
    • , Evelyn Fischer
    •  & Martin Reincke
  2. Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche Scientifique (UMRS) 970, Paris Cardiovascular Research Center, Paris, France.

    • Sheerazed Boulkroun
    • , Laurence Amar
    • , Benoit Samson-Couterie
    • , Pierre-Francois Plouin
    • , Xavier Jeunemaitre
    •  & Maria-Christina Zennaro
  3. Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

    • Sheerazed Boulkroun
    • , Laurence Amar
    • , Benoit Samson-Couterie
    • , Pierre-Francois Plouin
    • , Xavier Jeunemaitre
    •  & Maria-Christina Zennaro
  4. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.

    • Thomas Wieland
    • , Anett Walther
    • , Thomas Schwarzmayr
    • , Susanne Diener
    • , Elisabeth Graf
    • , Thomas Meitinger
    •  & Tim M Strom
  5. Department of Biomedicine, Aarhus University, Aarhus, Denmark.

    • Hang N Nielsen
    • , Vivien R Schack
    •  & Bente Vilsen
  6. Medizinische Zellbiologie, Universität Regensburg, Regensburg, Germany.

    • David Penton
    • , Philipp Tauber
    •  & Richard Warth
  7. Assistance Publique–Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.

    • Laurence Amar
    • , Pierre-Francois Plouin
    • , Xavier Jeunemaitre
    •  & Maria-Christina Zennaro
  8. Department of Medicine I, Endocrine and Diabetes Unit, University Hospital Würzburg, Würzburg, Germany.

    • Bruno Allolio
  9. Centre National de la Recherche Scientifique (CNRS), Institut des Hautes Etudes Scientifiques, Bures sur Yvette, France.

    • Arndt Benecke
  10. Clinical Endocrinology, Campus Mitte, University Hospital Charité, Berlin, Germany.

    • Marcus Quinkler
  11. Department of Medicine, University of Padova, Padova, Italy.

    • Francesco Fallo
  12. Endocrine Unit, Department of Medicine, University of Padova, Padova, Italy.

    • Franco Mantero
  13. Institute of Human Genetics, Technische Universität München, Munich, Germany.

    • Thomas Meitinger
    •  & Tim M Strom
  14. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.

    • Thomas Meitinger
  15. Department of Medical Sciences, Division of Internal Medicine and Hypertension, University of Torino, Turin, Italy.

    • Paolo Mulatero

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Contributions

S.B., H.N.N., U.D.L., D.P., V.R.S., A.W., P.T., S.D. and B.S.-C. performed the experiments. A.O., T.W., L.A., E.F., T.S., T.M.S., E.G. and A.B. performed statistical analysis and analyzed the data. B.A., M.Q., F.F., P.-F.P., F.M. and P.M. contributed materials. F.B., T.M., X.J., R.W., B.V., M.-C.Z., T.M.S. and M.R. jointly supervised research, conceived and designed the experiments, analyzed the data, contributed reagents, materials and/or analysis tools and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Felix Beuschlein or Martin Reincke.

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DOI

https://doi.org/10.1038/ng.2550