*3.3. Familial Hyperaldosteronism Type III*

Choi et al. identified the genetic basis of familial hyperaldosteronism type III (FH type III) in 2011 by next-generation sequencing [6]. A gain-of-function mutation in the *KCNJ5* gene (encoding the G-protein-coupled inwardly rectifying potassium channel GIRK4) was identified in the male index case and his two daughters. The mutation results in the substitution of a threonine residue (p.Thr158Ala) located just above the selectivity filter of the channel pore which interferes with the Thr158-Pro128 hydrogen bonding [6]. Patch clamp recordings of human embryonic kidney cells expressing the mutated GIRK4 p.Thr158Ala channel showed that the mutation results in a loss of selectivity for K+ and permissively allows the passage of Na<sup>+</sup> resulting in membrane depolarization [6]. In adrenal cells, membrane depolarization leads to the opening of voltage gated Ca2+ channels and Ca2+ influx activating the Ca2+ signalling pathway and aldosterone production. Expression of GIRK4 p.Thr158Ala in the human adrenocortical carcinoma cell line (HAC15) caused a marked increase in aldosterone secretion that was dependent on membrane depolarization and Na<sup>+</sup> and Ca2+ influx [19]. Until 2017, 22 patients with FH type III were described in the literature from 12 families [20]. Notable is that over half of the patients described with FH type III (14 of 22 cases occurring in 7 of 12 families) carried mutations of the Gly151 residue (p.Gly151Glu or p.Gly151Arg) in the GlyTyrGly motif implicated in K<sup>+</sup> selectivity [21].
