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

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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Figure 1: Summary of somatic alterations in ATP1A1 and ATP2B3 identified in APAs.
Figure 2: Structural positions of altered residues in Na+/K+ ATPase and Ca2+ ATPase.
Figure 3: Functional and electrophysiological examination of transfected cells and adenoma primary cultures.
Figure 4: Proposed mechanism for autonomous aldosterone secretion in APAs with somatic ATPase alterations.

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References

  1. Hannemann, A. et al. Screening for primary aldosteronism in hypertensive subjects: results from two German epidemiological studies. Eur. J. Endocrinol. 167, 7–15 (2012).

    Article  CAS  Google Scholar 

  2. Eide, I.K., Torjesen, P.A., Drolsum, A., Babovic, A. & Lilledahl, N.P. Low-renin status in therapy-resistant hypertension: a clue to efficient treatment. J. Hypertens. 22, 2217–2226 (2004).

    Article  CAS  Google Scholar 

  3. Rossi, G.P. et al. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J. Am. Coll. Cardiol. 48, 2293–2300 (2006).

    Article  CAS  Google Scholar 

  4. Choi, M. et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 331, 768–772 (2011).

    Article  CAS  Google Scholar 

  5. Boulkroun, S. et al. Prevalence, clinical, and molecular correlates of KCNJ5 mutations in primary aldosteronism. Hypertension 59, 592–598 (2012).

    Article  CAS  Google Scholar 

  6. Beuschlein, F. et al. Clonal composition of human adrenocortical neoplasms. Cancer Res. 54, 4927–4932 (1994).

    CAS  PubMed  Google Scholar 

  7. Gicquel, C. et al. Clonal analysis of human adrenocortical carcinomas and secreting adenomas. Clin. Endocrinol. 40, 465–477 (1994).

    Article  CAS  Google Scholar 

  8. Mulatero, P. et al. KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism. Hypertension 59, 235–240 (2012).

    Article  CAS  Google Scholar 

  9. Morth, J.P. et al. Crystal structure of the sodium-potassium pump. Nature 450, 1043–1049 (2007).

    Article  CAS  Google Scholar 

  10. Kaplan, J.H. Biochemistry of Na,K-ATPase. Annu. Rev. Biochem. 71, 511–535 (2002).

    Article  CAS  Google Scholar 

  11. Einholm, A.P., Andersen, J.P. & Vilsen, B. Importance of Leu99 in transmembrane segment M1 of the Na+,K+-ATPase in the binding and occlusion of K+. J. Biol. Chem. 282, 23854–23866 (2007).

    Article  CAS  Google Scholar 

  12. Yingst, D.R., Davis, J., Krenz, S. & Schiebinger, R.J. Insights into the mechanism by which inhibition of Na,K-ATPase stimulates aldosterone production. Metabolism 48, 1167–1171 (1999).

    Article  CAS  Google Scholar 

  13. Neri, G. et al. Ouabain chronic infusion enhances the growth and steroidogenic capacity of rat adrenal zona glomerulosa: the possible involvement of the endothelin system. Int. J. Mol. Med. 18, 315–319 (2006).

    CAS  PubMed  Google Scholar 

  14. Hajnóczky, G. et al. Angiotensin-II inhibits Na+/K+ pump in rat adrenal glomerulosa cells: possible contribution to stimulation of aldosterone production. Endocrinology 130, 1637–1644 (1992).

    PubMed  Google Scholar 

  15. Moseley, A.E. et al. Genetic profiling reveals global changes in multiple biological pathways in the hearts of Na,K-ATPase α1 isoform haploinsufficient mice. Cell Physiol. Biochem. 15, 145–158 (2005).

    Article  CAS  Google Scholar 

  16. Di Leva, F., Domi, T., Fedrizzi, L., Lim, D. & Carafoli, E. The plasma membrane Ca2+ ATPase of animal cells: structure, function and regulation. Arch. Biochem. Biophys. 476, 65–74 (2008).

    Article  CAS  Google Scholar 

  17. Street, V.A., McKee-Johnson, J.W., Fonseca, R.C., Tempel, B.L. & Noben-Trauth, K. Mutations in a plasma membrane Ca2+-ATPase gene cause deafness in deafwaddler mice. Nat. Genet. 19, 390–394 (1998).

    Article  CAS  Google Scholar 

  18. Schultz, J.M. et al. Modification of human hearing loss by plasma-membrane calcium pump PMCA2. N. Engl. J. Med. 352, 1557–1564 (2005).

    Article  CAS  Google Scholar 

  19. Åkerström, T. et al. Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter. PLoS ONE 7, e41926 (2012).

    Article  Google Scholar 

  20. Azizan, E.A. et al. Microarray, qPCR, and KCNJ5 sequencing of aldosterone-producing adenomas reveal differences in genotype and phenotype between zona glomerulosa– and zona fasciculata–like tumors. J. Clin. Endocrinol. Metab. 97, E819–E829 (2012).

    Article  CAS  Google Scholar 

  21. Ehret, G.B. et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478, 103–109 (2011).

    Article  CAS  Google Scholar 

  22. Spät, A. & Hunyady, L. Control of aldosterone secretion: a model for convergence in cellular signaling pathways. Physiol. Rev. 84, 489–539 (2004).

    Article  Google Scholar 

Download references

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.

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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.

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Correspondence to Felix Beuschlein or Martin Reincke.

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The authors declare no competing financial interests.

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Beuschlein, F., Boulkroun, S., Osswald, A. et al. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat Genet 45, 440–444 (2013). https://doi.org/10.1038/ng.2550

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