Somatic Mutations in Are Associated With Aldosterone-Producing Adenomas.

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 a pathological increase in aldosterone synthase 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 (encoding the cation-permeable channel, TRPML3). Electrophysiological, fura-2 calcium measurements, gene expression, and steroid quantification studies were performed in adrenal HAC15 cells to characterize the functional effects of the novel mutations.

RESULTS

Three somatic variants (p.Y391D, p.F415I, and p.N411_V412delinsI) were identified in aldosterone-producing adenomas from 4 male primary aldosteronism patients. Mutated 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 mutations in humans and the first to implicate mutated as a driver of dysregulated aldosterone production in primary aldosteronism.