At least 5% of individuals with hypertension have adrenal aldosterone-producing adenomas (APAs). Gain-of-function mutations in KCNJ5 and apparent loss-of-function mutations in ATP1A1 and ATP2A3 were reported to occur in APAs1,2. We find that KCNJ5 mutations are common in APAs resembling cortisol-secreting cells of the adrenal zona fasciculata but are absent in a subset of APAs resembling the aldosterone-secreting cells of the adrenal zona glomerulosa3. We performed exome sequencing of ten zona glomerulosa–like APAs and identified nine with somatic mutations in either ATP1A1, encoding the Na+/K+ ATPase α1 subunit, or CACNA1D, encoding Cav1.3. The ATP1A1 mutations all caused inward leak currents under physiological conditions, and the CACNA1D mutations induced a shift of voltage-dependent gating to more negative voltages, suppressed inactivation or increased currents. Many APAs with these mutations were <1 cm in diameter and had been overlooked on conventional adrenal imaging. Recognition of the distinct genotype and phenotype for this subset of APAs could facilitate diagnosis.

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Cambridge, UK. We are grateful to M. Gurnell for discussion and care of many of the patients, to N. Jamieson for all the laparoscopic adrenalectomies and to A. Marker for pathological diagnosis. We thank Dr. Yasmin for providing peripheral DNA samples from healthy, normotensive subjects. We thank R. Kuc and the Human Research Tissue Bank of Addenbrooke's Hospital, which is supported by the NIHR Cambridge BRC, for help with storage of fresh adrenal tissue for the Cambridge cohort; we particularly acknowledge B. Haynes, D. Walters, K. Brown, M. Elazoui, C. Karpinskyj, M. Bromwich and K. Payne. The work was funded by the British Heart Foundation (PG/07/085/23349), the Wellcome Trust (085686/Z/08/A), the NIHR Cambridge Biomedical Research Centre (Cardiovascular) and an NIHR Senior Investigator award to M.J.B. The work was also supported by the Austin Doyle Award funded by Servier Australia (to E.A.B.A.). C.A.B. is supported by the Wellcome Trust PhD program in Metabolic and Cardiovascular Disease. J.Z. is supported by the Cambridge Overseas Trust and the Sun Hung Kai Properties–Kwoks' Foundation PhD program. G.S.H.Y. was supported by European Union FP7-HEALTH-2009-241592 EurOCHIP and FP7-FOOD-266408 Full4Health. Aarhus, Denmark. We thank J. Egebjerg Jensen for discussion of the electrophysiology data. H.P. was supported by grants from The Carlsberg Foundation, The Lundbeck Foundation and L'Oréal/UNESCO. University of Innsbruck, Austria. The work was supported by the Austrian Science Fund (F44020). University College London, UK. We thank W. Pratt for technical assistance. The work was supported by the Wellcome Trust (098360/Z/12/Z). Hradec Kralove, Czech Republic. We thank A. Ryska, who selected the most appropriate adrenal samples for the Czech cohort. Funding is provided by program PRVOUK P037/03. Nijmegen, The Netherlands. We thank J.W.M. Lenders for introducing the collaboration and for his leading role in the recruitment of the Dutch cohort.

Author information

Author notes

    • Elena A B Azizan
    • , Hanne Poulsen
    • , Petronel Tuluc
    • , Junhua Zhou
    • , I Sadaf Farooqi
    • , Joerg Striessnig
    • , Poul Nissen
    •  & Morris J Brown

    These authors contributed equally to this work.


  1. Clinical Pharmacology Unit, Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.

    • Elena A B Azizan
    • , Junhua Zhou
    • , Carmela Maniero
    • , Lalarukh Haris Shaikh
    • , Cheryl A Brighton
    • , Ada E D Teo
    • , Anthony P Davenport
    •  & Morris J Brown
  2. Centre for Membrane Pumps in Cells and Disease—PUMPkin, Danish National Research Foundation, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.

    • Hanne Poulsen
    • , Michael V Clausen
    •  & Poul Nissen
  3. Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria.

    • Petronel Tuluc
    • , Andreas Lieb
    •  & Joerg Striessnig
  4. University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • Sumedha Garg
    • , Elena G Bochukova
    • , Giles S H Yeo
    •  & I Sadaf Farooqi
  5. Human Research Tissue Bank, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Addenbrooke's Hospital, Cambridge, UK.

    • Wanfeng Zhao
  6. Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Tanja Dekkers
    •  & Jaap Deinum
  7. Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Bas Tops
    •  & Benno Küsters
  8. 1st Department of Internal Medicine–Cardioangiology, Charles University Faculty of Medicine in Hradec Kralove and University Hospital Hradec Kralove, Hradec Kralove, Czech Republic.

    • Jiri Ceral
    •  & Miroslav Solar
  9. Cambridge National Institute for Health Research (NIHR) Biomedical Research Centre (BRC), Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, UK.

    • Sudeshna Guha Neogi
    •  & Ian McFarlane
  10. Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.

    • Nitzan Rosenfeld
    • , Francesco Marass
    •  & James Hadfield
  11. Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.

    • Wojciech Margas
    • , Kanchan Chaggar
    •  & Annette C Dolphin


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E.A.B.A. and M.J.B. designed and analyzed the adrenal experiments. H.P. and M.V.C. designed the electrophysiology experiments and performed cloning. H.P. performed and analyzed the electrophysiology experiments. M.V.C. made the homology model, and M.V.C., H.P. and P.N. discussed the structural analyses. A.C.D. and W.M. designed experiments on the Gly403Arg mutant of Cav1.3, undertaken by W.M. and K.C. K.C. performed protein blotting. P.T., A.L. and J.S. designed the experiments for the remaining Cav1.3 mutants. P.T. cloned the CACNA1D mutations, and A.L. performed whole-cell patch-clamp experiments. G.S.H.Y., S.G.N. and I.M. contributed to the design of RNA analyses, including for microarray analysis. E.G.B. and I.S.F. advised on the design and interpretation of exome sequencing. N.R., F.M. and J.H. designed and interpreted microfluidic sequencing. E.A.B.A. performed the H295R transfections with help from J.Z. J.Z. performed genotyping and Sanger sequencing with help from E.A.B.A., C.M., S.G. and E.G.B. Gene expression studies were performed by E.A.B.A., C.A.B., A.E.D.T., J.Z. and L.H.S. W.Z. performed immunohistochemistry, for which A.P.D. designed selective antisera to CYP11B1 and CYP11B2. For the Cambridge cohort, M.J.B., E.A.B.A., J.Z., C.M. and L.H.S. collected and prepared samples. For the Czech cohort, J.C. and M.S. collected and analyzed the clinical data, and E.A.B.A. and C.M. examined pathology, performed DNA isolation and prepared samples. For the Dutch cohort, J.D. executed the recruitment, B.K. examined pathology, B.T. performed DNA isolation, and T.D. prepared the samples. E.A.B.A. prepared the supplementary information, and I.S.F., J.S., H.P. and M.J.B. wrote the manuscript with comments from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Hanne Poulsen or Morris J Brown.

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