Rege, Juilee and Bandulik, Sascha and Nanba, Kazutaka and Kosmann, Carla and Blinder, Amy R. and Plain, Allein and Vats, Pankaj and Kumar-Sinha, Chandan and Lerario, Antonio M. and Else, Tobias and Yamazaki, Yuto and Satoh, Fumitoshi and Sasano, Hironobu and Giordano, Thomas J. and Williams, Tracy Ann and Reincke, Martin and Turcu, Adina F. and Udager, Aaron M. and Warth, Richard and Rainey, William E. (2023) Somatic SLC30A1 mutations altering zinc transporter ZnT1 cause aldosterone-producing adenomas and primary aldosteronism. NATURE GENETICS, 66. pp. 1623-1631. ISSN 1061-4036, 1546-1718
Full text not available from this repository. (Request a copy)Abstract
Primary aldosteronism (PA) is the most common form of endocrine hypertension and is characterized by inappropriately elevated aldosterone production via a renin-independent mechanism. Driver somatic mutations for aldosterone excess have been found in approximately 90% of aldosterone-producing adenomas (APAs). Other causes of lateralized adrenal PA include aldosterone-producing nodules (APNs). Using next-generation sequencing, we identified recurrent in-frame deletions in SLC30A1 in four APAs and one APN (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 close to the zinc-binding site (His43 and Asp47) in transmembrane domain II and probably cause abnormal ion transport. Cases of PA with SLC30A1 mutations showed male dominance and demonstrated increased aldosterone and 18- oxocortisol concentrations. Functional studies of the SLC30A151_57del variant in a doxycycline-inducible adrenal cell system revealed pathological Na+ influx. An aberrant Na+ current led to depolarization of the resting membrane potential and, thus, to the opening of voltage-gated calcium (Ca2+) channels. This resulted in an increase in cytosolic Ca2+ activity, which stimulated CYP11B2 mRNA expression and aldosterone production. Collectively, these data implicate zinc transporter alterations as a dominant driver of aldosterone excess in PA.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PRIMARY HYPERALDOSTERONISM; STEROIDOGENIC ENZYMES; CHANNEL MUTATIONS; CALCIUM-CHANNELS; PREVALENCE; HYPERTENSION; EXPRESSION; ATP1A1; MUTANT; 18-OXOCORTISOL |
| Subjects: | 500 Science > 580 Botanical sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Pflanzenwissenschaften > Lehrstuhl für Zellbiologie und Pflanzenphysiologie (Prof. Dr. Klaus Grasser) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 May 2024 08:20 |
| Last Modified: | 14 May 2024 09:17 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60686 |
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