Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension

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  • Elena A B Azizan, Clinical Pharmacology Unit, Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Storbritannien
  • Hanne Poulsen
  • Petronel Tuluc, Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences, University of Innsbruck, Østrig
  • Junhua Zhou, Clinical Pharmacology Unit, Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Storbritannien
  • Michael Clausen, National Veterinary Institute, Danmark
  • Andreas Lieb, Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences, University of Innsbruck, Østrig
  • Carmela Maniero, Clinical Pharmacology Unit, Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Storbritannien
  • Sumedha Garg, University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Storbritannien
  • Elena G Bochukova, University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Storbritannien
  • Wanfeng Zhao, Human Research Tissue Bank, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Addenbrooke's Hospital, Storbritannien
  • Lalarukh Haris Shaikh, Clinical Pharmacology Unit, Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Storbritannien
  • Cheryl A Brighton, Clinical Pharmacology Unit, Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Storbritannien
  • Ada E D Teo, Clinical Pharmacology Unit, Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Storbritannien
  • Anthony P Davenport, Clinical Pharmacology Unit, Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Storbritannien
  • Tanja Dekkers, Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Holland
  • Bas Tops, Department of Pathology, Radboud University Nijmegen Medical Centre, Holland
  • Benno Küsters, Department of Pathology, Radboud University Nijmegen Medical Centre, Storbritannien
  • Jiri Ceral, 1st Department of Internal Medicine–Cardioangiology, Charles University Faculty of Medicine in Hradec Kralove and University Hospital Hradec Kralove, Tjekkiet
  • Giles S H Yeo, University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Storbritannien
  • Sudeshna Guha Neogi, Cambridge National Institute for Health Research (NIHR) Biomedical Research Centre (BRC), Department of Clinical Biochemistry, Addenbrooke's Hospital, Storbritannien
  • Ian McFarlane, Cambridge National Institute for Health Research (NIHR) Biomedical Research Centre (BRC), Department of Clinical Biochemistry, Addenbrooke's Hospital, Storbritannien
  • Nitzan Rosenfeld, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Storbritannien
  • Francesco Marass, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Storbritannien
  • James Hadfield, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Storbritannien
  • Wojciech Margas, Department of Neuroscience, Physiology and Pharmacology, University College London, Storbritannien
  • Kanchan Chaggar, Department of Neuroscience, Physiology and Pharmacology, University College London, Storbritannien
  • Miroslav Solar, 1st Department of Internal Medicine–Cardioangiology, Charles University Faculty of Medicine in Hradec Kralove and University Hospital Hradec Kralove, Tjekkiet
  • Jaap Deinum, Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Holland
  • Annette C Dolphin, Department of Neuroscience, Physiology and Pharmacology, University College London, Storbritannien
  • I Sadaf Farooqi, University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Storbritannien
  • Joerg Striessnig, Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences, University of Innsbruck, Østrig
  • Poul Nissen
  • Morris J Brown, Clinical Pharmacology Unit, Centre for Clinical Investigation, Addenbrooke's Hospital, University of Cambridge, Storbritannien
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
OriginalsprogEngelsk
TidsskriftNature Genetics
Vol/bind45
Nummer9
Sider (fra-til)1055-1060
Antal sider6
ISSN1061-4036
DOI
StatusUdgivet - 28 aug. 2013

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