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Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production

Wu X 1 , Azizan EAB 2 , Goodchild E 1 , Garg S 1 , Hagiyama M 3 , Cabrera CP 4 Show all authors , Fernandes-Rosa FL 5 , Boulkroun S 5 , Kuan JL 6 , Tiang Z 6 , David A 7 , Murakami M 8 , Mein CA 9 , Wozniak E 9 , Zhao W 10 , Marker A 10 , Buss F 11 , Saleeb RS 12 , Salsbury J 1 , Tezuka Y 13 , Satoh F 13 , Oki K 14 , Udager AM 15 , Cohen DL 16 , Wachtel H 17 , King PJ 18 , Drake WM 4 , Gurnell M 19 , Ceral J 20 , Ryska A 21 , Mustangin M 22 , Wong YP 22 , Tan GC 22 , Solar M 20 , Reincke M 8 , Rainey WE 23 , Foo RS 6 , Takaoka Y 24 , Murray SA 25 , Zennaro MC 5 , Beuschlein F 26 , Ito A 3 , Brown MJ 27

Affiliations 

  • 1 Endocrine Hypertension, Department of Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK
  • 2 Endocrine Hypertension, Department of Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK. [email protected]
  • 3 Department of Pathology, Faculty of Medicine, Kindai University, Osakasayama, Japan
  • 4 NIHR Barts Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  • 5 Université Paris Cité, PARCC, Inserm, Paris, France
  • 6 Cardiovascular Disease Translational Research Programme, Department of Medicine, National University of Singapore, Singapore, Singapore
  • 7 Centre for Bioinformatics, Department of Life Sciences, Imperial College London, London, UK
  • 8 Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany
  • 9 Barts and London Genome Centre, School of Medicine and Dentistry, Blizard Institute, London, UK
  • 10 Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK
  • 11 Cambridge Institute for Medical Research, The Keith Peters Building, University of Cambridge, Cambridge, UK
  • 12 Centre for Microvascular Research, William Harvey Research Institute, Queen Mary University of London, London, UK
  • 13 Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Hospital, Sendai, Japan
  • 14 Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
  • 15 Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
  • 16 Renal Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
  • 17 Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
  • 18 Department of Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK
  • 19 Metabolic Research Laboratories, Welcome Trust-MRC Institute of Metabolic Science, and NIHR Cambridge Biomedical Research Centre, Cambridge Biomedical Campus, Cambridge, UK
  • 20 1st Department of Internal Medicine-Cardioangiology, Charles University Faculty of Medicine in Hradec Kralove and University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
  • 21 Department of Pathology, Charles University Faculty of Medicine in Hradec Kralove and University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
  • 22 Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
  • 23 Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
  • 24 Department of Computational Drug Design and Mathematical Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyoma, Japan
  • 25 Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
  • 26 Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, UniversitätsSpital Zürich (USZ) und Universität Zürich (UZH), Zurich, Switzerland
  • 27 Endocrine Hypertension, Department of Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK. [email protected]
Nat Genet, 2023 Jun;55(6):1009-1021.
PMID: 37291193 DOI: 10.1038/s41588-023-01403-0

Abstract

Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n = 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2 (aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1 cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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