Primary 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 in SLC30A1 in five APAs (p.L51_A57del, n=3; p.L49_L55del, n=2). SLC30A1 encodes the ubiquitous zinc efflux transporter ZnT1 (zinc transporter 1). The identified SLC30A1 variants 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 unique SLC30A1 mutations showed male dominance and demonstrated increased aldosterone and 18-oxo-cortisol concentrations. Functional studies of the mutant SLC30A151_57del variant 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 stimulated CYP11B2 mRNA expression and aldosterone production. Collectively, these data implicate the first-in-field zinc transporter mutations as a dominant driver of aldosterone excess in PA.
Authors: Juilee Rege, Kazutaka Nanba, Sascha Bandulik, Carla Kosmann, Amy R. Blinder, Pankaj Vats, Chandan Kumar-Sinha, Antonio M. Lerario, Tobias Else, Yuto Yamazaki, Fumitoshi Satoh, Hironobu Sasano, Thomas J. Giordano, Tracy Ann Williams, Martin Reincke, Adina F. Turcu, Aaron M. Udager, Richard Warth, William E. Rainey
Keywords: somatic mutation, SLC30A1, zinc efflux transporter, ZnT1
DOI Number: 10.1101/2022.07.25.501443 Publication Year: 2022
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