Somatic Mutations in in Aldosterone-Producing Adenomas cause Primary Aldosteronism.

UNLABELLED

Primary aldosteronism is characterized by renin-independent hyperaldosteronism that originates from aldosterone-producing lesions in the adrenal glands. Under physiological conditions, aldosterone synthase ( ) expression is confined to the adrenal zona glomerulosa where it catalyzes the final reaction yielding aldosterone. The regulation of transcription depends on the control of cellular membrane potential and cytosolic calcium activity. In primary aldosteronism, aldosterone-producing adenomas (APAs) are characterized by disrupted regulation of CYP11B2 expression resulting in autonomous biosynthesis of aldosterone. These lesions often harbor aldosterone-driver somatic mutations in genes encoding ion transporters/channels/pumps that increase cytosolic calcium activity causing increased expression and aldosterone biosynthesis. We investigated APAs devoid of known somatic mutations and detected a missense mutation and a deletion-insertion variant in which encodes for mucolipin-3 (TRPML3) - a highly conserved inwardly-rectifying, cation-permeable channel. These mutations were identified in three APAs derived from male patients with primary aldosteronism: p. Y391D and p.N411_V412delinsI. Both mutations are located near the ion pore and selectivity filter of TRPML3. This is the first report of disease-causing mutations in humans. Functional studies suggest might directly or indirectly via membrane depolarization alter calcium influx of transfected adrenocortical cells, resulting in increased transcription and aldosterone production. This study implicates mutated as a driver of aldosterone excess in primary aldosteronism.

SIGNIFICANCE STATEMENT

Primary aldosteronism is a common but under-diagnosed endocrine disease that contributes to global hypertension burden and cardiovascular mortality and morbidity. Hyperaldosteronism in primary aldosteronism is mainly caused by adrenal lesions harboring somatic mutations that disrupt intracellular calcium levels and consequently aldosterone synthase expression and aldosterone production. Majority of these mutations have been identified in genes encoding ion transporters/channels/pumps. Herein, we report the first disease-causing somatic mutations in human in aldosterone-producing adenomas (APAs) devoid of known mutations. investigations showed the variant (p.Y391D) caused an influx of cytosolic calcium in adrenocortical cells and the subsequent increase in aldosterone synthase and aldosterone biosynthesis.