Somatic Mutations in MCOLN3 Are Associated with Aldosterone-Producing Adenomas

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.