Zinc transporter somatic gene mutations cause primary aldosteronism

Abstract

AbstractPrimary aldosteronism (PA) is the most common form of endocrine hypertension and effects one in 50 adults. PA is characterized by inappropriately elevated aldosterone production via renin-independent mechanisms. Driver somatic mutations for aldosterone excess have been found in approximately 90% of aldosterone-producing adenomas (APAs). Using next-generation sequencing, we identified recurrent in-frame deletions inSLC30A1in five APAs (p.L51_A57del, n=3; p.L49_L55del, n=2).SLC30A1encodes the ubiquitous zinc efflux transporter ZnT1 (zinc transporter 1). The identifiedSLC30A1variants are situated in close proximity of the zincbinding site (H43 and D47) in transmembrane domain II and likely cause abnormal ion transport. PA cases with the uniqueSLC30A1mutations showed male dominance and demonstrated increased aldosterone and 18-oxo-cortisol concentrations. Functional studies of the mutant SLC30A151_57delvariant in a doxycycline-inducible adrenal cell system revealed abnormal Na+conductivity caused by the mutant, which in turn led to the depolarization of the resting membrane potential, and thus to the opening of voltage-gated calcium channels. This resulted in an increase in cytosolic Ca2+activity, which stimulatedCYP11B2mRNA expression and aldosterone production. Collectively, these data implicate the first-in-field zinc transporter mutations as a dominant driver of aldosterone excess in PA.