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Somatic SLC30A1 mutations altering zinc transporter ZnT1 cause aldosterone-producing adenomas and primary aldosteronism.
- Source :
-
Nature genetics [Nat Genet] 2023 Oct; Vol. 55 (10), pp. 1623-1631. Date of Electronic Publication: 2023 Sep 14. - Publication Year :
- 2023
-
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&#95;A57del, nā=ā3; p.L49&#95;L55del, nā=ā2). 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 SLC30A1 <superscript>51&#95;57del</superscript> variant in a doxycycline-inducible adrenal cell system revealed pathological Na <superscript>+</superscript> influx. An aberrant Na <superscript>+</superscript> current led to depolarization of the resting membrane potential and, thus, to the opening of voltage-gated calcium (Ca <superscript>2+</superscript> ) channels. This resulted in an increase in cytosolic Ca <superscript>2+</superscript> 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.<br /> (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Subjects :
- Male
Humans
Aldosterone genetics
Mutation
Zinc metabolism
G Protein-Coupled Inwardly-Rectifying Potassium Channels genetics
G Protein-Coupled Inwardly-Rectifying Potassium Channels metabolism
Adrenocortical Adenoma genetics
Hyperaldosteronism genetics
Adenoma genetics
Adenoma complications
Adrenal Cortex Neoplasms genetics
Cation Transport Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1546-1718
- Volume :
- 55
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Nature genetics
- Publication Type :
- Report
- Accession number :
- 37709865
- Full Text :
- https://doi.org/10.1038/s41588-023-01498-5