Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

TLDR

Primary aldosteronism is the most common adrenal disorder causing secondary hypertension, yet the cellular origins of aldosterone production remain poorly understood, with recent observations of subcapsular aldosterone‑producing cell clusters in normal adrenals. The authors hypothesize that these APCCs contribute to the development of primary aldosteronism. Transcriptomic analysis revealed that APCCs exhibit elevated CYP11B2 expression and harbor APA‑associated ion‑channel/pump mutations distinct from those in adenomas, supporting their role as precursors of primary aldosteronism.

Abstract

Significance Primary aldosteronism (PA) represents the most common adrenal disease and cause of secondary hypertension. However, little is known regarding adrenal cellular origins. Recently, subcapsular aldosterone-producing cell clusters (APCCs) were observed in normal adrenals. We hypothesize that APCCs are a contributor to PA. Here, we characterized the APCC transcriptome and show that CYP11B2 expression is increased compared with the rest of the adrenal cortex. We also show that many APCCs harbor known aldosterone-producing adenoma (APA)-related ion channels/pumps ( ATPase, Na + /K + transporting, α1-polypeptide and calcium channel, voltage-dependent, L-type, α1D-subunit ) mutations that stimulate CYP11B2 expression and aldosterone production. Importantly, the mutation spectrum seen in APCCs differs from that reported for APA. These results provide molecular support for APCC as a precursor of PA.