Aldosterone-producing adenomas; genetics

In 2011, using exomes sequencing Choi et al. in about 34% of 22 aldosterone-producing adenoma (APA) discovered mutations in the selectivity filter of the KCNJ5 gene, which codes for the Kir3.4 K+ channel. This channel is highly expressed in the aldosterone-producing cells of the zona glomerulosa (ZG) and plays a key role in maintaining cell hyperpolarized (Fig. 1, Panels A and B). The Authors identified two recurrent functional variants (G151R and L168R) in this highly conserved region of the K+ channel, which allows the exit of K+ from the cells in a selective fashion, for example, with exclusion of other ions. Using cloning techniques and site-directed mutagenesis they could show that mutant-transfected cells in vitro exhibit perturbation in both size and charge of the selectivity filter, resulting in permeability to Na+, Na+ influx, and membrane depolarization. After this discovery other mutations in APA were found. Practically all of them result in increased cytosolic calcium with ensuing activation of the biosynthesis of aldosterone. These somatic mutations are herein described along with their functional consequences and the mechanisms whereby they lead to hyperaldosteronism.