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.

1st Department of Internal Medicine Cardioangiology Charles University Faculty of Medicine in Hradec Kralove and University Hospital Hradec Kralove Hradec Kralove Czech Republic

Assistance Publique Hôpitaux de Paris Hôpital Européen Georges Pompidou Service de Génétique Paris France

Barts and London Genome Centre School of Medicine and Dentistry Blizard Institute London UK

Cambridge Institute for Medical Research The Keith Peters Building University of Cambridge Cambridge UK

Cardiovascular Disease Translational Research Programme Department of Medicine National University of Singapore Singapore Singapore

Centre for Bioinformatics Department of Life Sciences Imperial College London London UK

Centre for Microvascular Research William Harvey Research Institute Queen Mary University of London London UK

Centre for Translational Bioinformatics William Harvey Research Institute Queen Mary University of London London UK

Clinical Pharmacology Unit University of Cambridge Cambridge UK

Department of Cell Biology University of Pittsburgh School of Medicine Pittsburgh PA USA

Department of Computational Drug Design and Mathematical Medicine Graduate School of Medicine and Pharmaceutical Sciences University of Toyama Toyoma Japan

Department of Endocrinology William Harvey Research Institute Queen Mary University of London London UK

Department of Histopathology Addenbrooke's Hospital Cambridge UK

Department of Medicine Faculty of Medicine Universiti Kebangsaan Malaysia Kuala Lumpur Malaysia

Department of Molecular and Internal Medicine Graduate School of Biomedical and Health Sciences Hiroshima University Hiroshima Japan

Department of Pathology Charles University Faculty of Medicine in Hradec Kralove and University Hospital Hradec Kralove Hradec Kralove Czech Republic

Department of Pathology Faculty of Medicine Kindai University Osakasayama Japan

Department of Pathology Faculty of Medicine Universiti Kebangsaan Malaysia Kuala Lumpur Malaysia

Department of Pathology University of Michigan Medical School Ann Arbor MI USA

Department of Surgery Hospital of the University of Pennsylvania Philadelphia PA USA

Division of Clinical Hypertension Endocrinology and Metabolism Tohoku University Graduate School of Medicine Sendai Japan

Division of Metabolism Endocrinology and Diabetes University of Michigan Ann Arbor MI USA

Division of Nephrology Endocrinology and Vascular Medicine Tohoku University Hospital Sendai Japan

Endocrine Hypertension Department of Clinical Pharmacology and Precision Medicine William Harvey Research Institute Queen Mary University of London London UK

Klinik für Endokrinologie Diabetologie und Klinische Ernährung UniversitätsSpital Zürich Zurich Switzerland

Medizinische Klinik und Poliklinik 4 Klinikum der Universität Ludwig Maximilians Universität München Munich Germany

Metabolic Research Laboratories Welcome Trust MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre Cambridge Biomedical Campus Cambridge UK

NIHR Barts Biomedical Research Centre Barts and The London School of Medicine and Dentistry Queen Mary University of London London UK

Renal Division Department of Medicine Perelman School of Medicine at the University of Pennsylvania Philadelphia PA USA

St Bartholomew's Hospital Barts Health NHS Trust London UK

Université Paris Cité PARCC Inserm Paris France

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