Somatic Mutations in MCOLN3 Are Associated with Aldosterone-Producing Adenomas

ABSTRACT: Background: Primary aldosteronism is a common but underdiagnosed cause of endocrine hypertension that contributes to global cardiovascular morbidity and mortality. It is characterized by renin-independent hyperaldosteronism that originates from adrenal lesions — the majority of which are found to harbor aldosterone-driver somatic mutations in genes encoding ion-transporting proteins. These mutations disrupt intracellular calcium homeostasis, facilitating pathologic increase in aldosterone synthase (CYP11B2) expression and aldosterone production. Elucidating the exact mechanisms causing aldosterone excess in primary aldosteronism would further the development of targeted treatments and alleviate the global hypertension burden.Methods: Next-generation sequencing analysis of formalin-fixed paraffin-embedded aldosterone-producing adenomas identified novel somatic variants in MCOLN3 (encoding the cation-permeable channel, TRPML3). Electrophysiologic, fura-2 calcium measurements, gene expression and steroid quantification studies were performed in adrenal HAC15 cells to characterize the functional effects of the novel MCOLN3 mutations. Results: Three somatic MCOLN3 variants (p.Y391D, p.F415I and p.N411_V412delinsI) were identified in four aldosterone-producing adenomas from male primary aldosteronism patients. Mutated MCOLN3 expressed in HAC15 cells resulted in a gain-of-function phenotype, which induced cell membrane depolarization and calcium influx and, in turn, triggered a significant increase in aldosterone synthase expression and aldosterone production. Conclusions: This is the first report of disease-causing MCOLN3 mutations in humans and first to implicate mutated MCOLN3 as a driver of dysregulated aldosterone production in primary aldosteronism.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299739 | GEO | 2026/06/13

REPOSITORIES: GEO