| Autor: |
Rege, Juilee, Bandulik, Sascha, Nanba, Kazutaka, Kosmann, Carla, Blinder, Amy R., Plain, Allein, Vats, Pankaj, Kumar-Sinha, Chandan, Lerario, Antonio M., Else, Tobias, Yamazaki, Yuto, Satoh, Fumitoshi, Sasano, Hironobu, Giordano, Thomas J., Williams, Tracy Ann, Reincke, Martin, Turcu, Adina F., Udager, Aaron M., Warth, Richard, Rainey, William E. |
| Zdroj: |
Nature Genetics; October 2023, Vol. 55 Issue: 10 p1623-1631, 9p |
| Abstrakt: |
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 SLC30A1in four APAs and one APN (p.L51_A57del, n= 3; p.L49_L55del, n= 2). SLC30A1encodes the ubiquitous zinc efflux transporter ZnT1 (zinc transporter 1). The identified SLC30A1variants 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 SLC30A1mutations showed male dominance and demonstrated increased aldosterone and 18-oxocortisol concentrations. Functional studies of the SLC30A151_57delvariant 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 CYP11B2mRNA expression and aldosterone production. Collectively, these data implicate zinc transporter alterations as a dominant driver of aldosterone excess in PA. |
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