Zinc transporter somatic gene mutations cause primary aldosteronism

Author:

Rege JuileeORCID,Nanba KazutakaORCID,Bandulik SaschaORCID,Kosmann Carla,Blinder Amy R.,Vats Pankaj,Kumar-Sinha Chandan,Lerario Antonio M.,Else TobiasORCID,Yamazaki Yuto,Satoh FumitoshiORCID,Sasano HironobuORCID,Giordano Thomas J.,Williams Tracy Ann,Reincke MartinORCID,Turcu Adina F.,Udager Aaron M.,Warth Richard,Rainey William E.

Abstract

AbstractPrimary 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 inSLC30A1in five APAs (p.L51_A57del, n=3; p.L49_L55del, n=2).SLC30A1encodes the ubiquitous zinc efflux transporter ZnT1 (zinc transporter 1). The identifiedSLC30A1variants 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 uniqueSLC30A1mutations showed male dominance and demonstrated increased aldosterone and 18-oxo-cortisol concentrations. Functional studies of the mutant SLC30A151_57delvariant 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 stimulatedCYP11B2mRNA expression and aldosterone production. Collectively, these data implicate the first-in-field zinc transporter mutations as a dominant driver of aldosterone excess in PA.

Publisher

Cold Spring Harbor Laboratory

Cited by 5 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Primary aldosteronism: molecular medicine meets public health;Nature Reviews Nephrology;2023-08-23

2. Primary Aldosteronism;Endocrinology;2023

3. Adrenal Anion Channels: New Roles in Zona Glomerulosa Physiology and in the Pathophysiology of Primary Aldosteronism;Anion Channels and Transporters;2023

4. CaV3.2 (CACNA1H) in Primary Aldosteronism;Voltage-gated Ca2+ Channels: Pharmacology, Modulation and their Role in Human Disease;2023

5. Primary Aldosteronism;Endocrinology;2023

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