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

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.

Automated Annotation of Disease Subtypes

“…-Cardiovascular risk and Diabetes : both of these disease families have different risk factors, including environmental, genetic and genetic-environment interaction (GxE). For example, Type 1 vs Type 2 diabetes, or specific genetic risk factors [6], [15].…”

Progress in Primary Aldosteronism 7: No better time to meet!

“…Following the recovery in 2022, we believed that the ideal time had come to reconvene. Major progress had been made during the past years, and key publications have addressed new genetic events [2][3][4][5][6][7], diagnosis [8,9] pathophysiology of aldosterone excess [10][11][12][13][14][15], imaging [16], histopathologic classifications [17], and treatment [18] but unresolved and controversial issues remain. In October 2022, PIPA 7 took place in the usual location at Castle Nymphenburg in Munich.…”

Single-Nucleus Analysis Reveals Tumor Heterogeneity of Aldosterone-Producing Adenoma

“…In particular, exome sequencing has contributed to uncovering several genes (including KCNJ5, ATP1A1, ATP2B3, CACNA1D, CAC-NA1H, CTNNB1, GNAQ, GNA11, CLCN2, CADM1, and SLC30A1), the specific mutations of which are associated with autonomous aldosterone production. [9][10][11][12][13][14][15][16][17] Recently, single-cell RNA sequencing technology, which examines the cellular composition and features, and functions of tumor cells, has been increasingly applied to study the occurrence and development of diseases at the cellular level. 18 However, reports on the use of single-cell RNA sequencing or single-nucleus RNA sequencing (snRNA-seq) in studying the adrenal tissue, such as the identification of aldosterone-producing cell clusters at the single-cell level in the examination of normal human adrenal tissue, 19 a thorough investigation of immune cells in the analysis of APA tissue, 20 and the clustering analysis to identify the localization of diseasespecific genes in peritumoral adrenal cortex tissues, 21 are limited.…”

“…In particular, exome sequencing has contributed to uncovering several genes (including KCNJ5 , ATP1A1 , ATP2B3 , CACNA1D , CACNA1H , CTNNB1 , GNAQ , GNA11 , CLCN2 , CADM1 , and SLC30A1 ), the specific mutations of which are associated with autonomous aldosterone production. 9–17…”