Somatic Mutations in MCOLN3 in Aldosterone-Producing Adenomas cause Primary Aldosteronism.

Abstract

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 MCOLN3 in aldosterone-producing adenomas (APAs) devoid of known mutations. In vitro investigations showed the MCOLN3 variant (p.Y391D) caused an influx of cytosolic calcium in adrenocortical cells and the subsequent increase in aldosterone synthase and aldosterone biosynthesis.