Year: 2022
Type: preprint
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 SLC30A1 51_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 Ca 2+ 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
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Doris Duke Charitable Foundation, American Heart Association, University of Michigan, Deutsche Forschungsgemeinschaft, Universität Regensburg, National Institutes of Health, Michigan Institute for Clinical and Health Research, University of Michigan Center for Gastrointestinal Research, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences, H2020 European Research Council
Awards: G1012675691, G1051102796, G1549322469, G2049072053, G2290386743, G2498617192, G2507118478, G2580128945, G2633661240, Molekulare Mechanismen der Tumorentstehung beim primären Aldosteronismus, G2757709669, G3084907704, Adrenal Origins of Aldosterone Excess, G3683493992, G3879852479, G4130391418, G4151812806, G4153656625, G4338912026, Michigan Institute for Clinical and Health Research (MICHR), G4484641000, G4538523901, G467313275, G5044915050, Pathophysiology of Primary Aldosteronism, G5270713371, G5524841655, G5614808758, G5836462021, G6295273581, The Genetics of Primary Aldosteronism, Novel Genetic Causes of Endocrine Hypertension, G6709029143, G7208031763, G7250270527, G748338812, G8143140658, Mechanisms Leading to Adrenal Zonation, Genetic Causes of Primary Aldosteronism in African Americans
OpenAlex ID: W4287877598