What does this research mean for the field?

Somatic mutations in the CADM1 gene cause reversible hypertension by disrupting gap junction communication, which normally suppresses physiological aldosterone production. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.ESTABLISHES_NEW_DIRECTION.

June 1, 2023Nature Genetics60 citationsOpen Access

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

XWXilin WuSt Bartholomew's Hospital EAElena AzizanQueen Mary University of London EGEmily GoodchildSt Bartholomew's Hospital

Structured PICO

Do somatic mutations in CADM1 increase aldosterone production in preclinical models of aldosterone-producing adenomas?

Population

417 aldosterone-producing adenomas (APAs) from patients with primary aldosteronism across multiple cohorts (UK, Japan, Germany, France, US), and preclinical models including human adrenocortical H295R cells, HEK293T cells, and mouse 3T3 cells.

Intervention

CADM1 somatic mutations (p.Val380Asp or p.Gly379Asp), CADM1 knockdown via shRNA, or gap junction blockade by Gap27

Comparator

Wild-type CADM1, empty vector, or non-targeting shRNA

Outcome

CYP11B2 (aldosterone synthase) expression and aldosterone productionsurrogate

Somatic mutations in the CADM1 gene cause primary aldosteronism and reversible hypertension by inhibiting gap junction communication and upregulating aldosterone synthase.

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.

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