Abstract
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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Disclosure Statement: The authors have nothing to disclose.
Funding: This work was supported by grants from NIDDK (R01DK106618 and R01DK043140 to W.E.R.), NCATS/ Michigan Institute for Clinical and Health Research (UL1TR002240 to J.R.), NHLBI (1R01HL130106 to T.E, and R01HL155834 to A.F.T.), the Doris Duke Charitable Foundation (2019087 to A.F.T), the American Heart Association (17SDG33660447 to K.N. and 20CDA35320016 to J.R.), the Ministry of Health, Labour, and Welfare, Japan (20FC1020 to H.S.). and the Deutsche Forschungsgemeinschaft (WA 1275/6 to R.W., BA 4436/2-1 to S.B., CRC/TRR 205 “The Adrenal Gland”, RE 752/31-1 and WI 5359/2-1 “Project 444776998” to M.R. and T.A.W). M.R. also received funding from the Else Kröner-Fresenius Stiftung (2012_A103, 2015_A228, and 2019_A104 “Else-Kröner Hyperaldosteronismus-German Conn Registry”), and the European Research Council (Grant # 694913).