Andreas Lieb, Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences, University of Innsbruck, Austria
Carmela Maniero, University of Cambridge, United Kingdom
Sumedha Garg, University of Cambridge, United Kingdom
Elena G Bochukova, University of Cambridge, United Kingdom
Wanfeng Zhao, University of Cambridge, United Kingdom
Lalarukh Haris Shaikh, University of Cambridge, United Kingdom
Cheryl A Brighton, University of Cambridge, United Kingdom
Ada E D Teo, University of Cambridge, United Kingdom
Anthony P Davenport, University of Cambridge, United Kingdom
Tanja Dekkers, Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Netherlands
Bas Tops, Department of Pathology, Radboud University Nijmegen Medical Centre, Netherlands
Benno Küsters, Department of Pathology, Radboud University Nijmegen Medical Centre, United Kingdom
Jiri Ceral, 1st Department of Internal Medicine–Cardioangiology, Charles University Faculty of Medicine in Hradec Kralove and University Hospital Hradec Kralove, Czech Republic
Giles S H Yeo, University of Cambridge, United Kingdom
Sudeshna Guha Neogi, Cambridge National Institute for Health Research (NIHR) Biomedical Research Centre (BRC), Department of Clinical Biochemistry, Addenbrooke's Hospital, United Kingdom
Ian McFarlane, Cambridge National Institute for Health Research (NIHR) Biomedical Research Centre (BRC), Department of Clinical Biochemistry, Addenbrooke's Hospital, United Kingdom
Nitzan Rosenfeld, University of Cambridge, United Kingdom
Francesco Marass, University of Cambridge, United Kingdom
James Hadfield, University of Cambridge, United Kingdom
Wojciech Margas, Department of Neuroscience, Physiology and Pharmacology, University College London, United Kingdom
Kanchan Chaggar, Department of Neuroscience, Physiology and Pharmacology, University College London, United Kingdom
Miroslav Solar, 1st Department of Internal Medicine–Cardioangiology, Charles University Faculty of Medicine in Hradec Kralove and University Hospital Hradec Kralove, Czech Republic
Jaap Deinum, Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Netherlands
Annette C Dolphin, Department of Neuroscience, Physiology and Pharmacology, University College London, United Kingdom
I Sadaf Farooqi, University of Cambridge, United Kingdom
Joerg Striessnig, Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences, University of Innsbruck, Austria
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 APAs. 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 glomerulosa. 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