ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Nat Genet. 2018; 50(3): 355-361

[Comments on 8.1 and 8.2] Primary aldosteronism (PA) is the most common form of secondary hypertension, affecting 3–5% of the general hypertensive population and 8–10% of patients referred to specialist hypertension services, although it is very rare in children (1). In comparison to essential hypertension, increased aldosterone concentrations in PA are associated with increased cardiovascular risk (probably due to MR expressed in endothelial, vascular smooth muscle and immune cells) in particular coronary artery disease, heart failure, renal damage and stroke (2). The main causes of PA are bilateral adrenal hyperplasia (BAH) and unilateral aldosterone-producing adrenal adenoma (APA), whereas inherited forms of PA, such as familial hyperaldosteronism (FH) type 1 and 3, account for fewer than 1% of cases. Gain-of-function mutations in different genes, encoding cation channels (KCNJ5, CACNA1D, CACNA1H) and ATPases (ATP1A1, ATP2B3), regulating intracellular ion homeostasis and plasma membrane potential, have been described in APAs and familial forms of PA, but the pathophysiology of many cases is still unknown.

In 1992, Stowasser et al. described a multiplex kindred with autosomal dominant PA that was clinically distinct from FH-I, and hence called it FH-II (3). The responsible gene in this kindred had not been identified. In the first study by Scholl et al., the authors recruited an additional affected individual of this kindred and performed exome sequencing of 3 affected subjects. They also analyzed 80 additional probands with unsolved early-onset PA. 8 probands had novel heterozygous variants in CLCN2, including 2 de novo mutations and 4 independent occurrences of a mutation encoding an identical p.Arg172Gln substitution; all relatives with early-onset PA carried the CLCN2 variant found in the proband. In the second study by Fernandes-Rosa et al, the authors performed whole-exome sequencing in patients with early-onset PA and identified a de novo heterozygous c.71G>A/p.Gly24Asp mutation in the CLCN2 gene, encoding the voltage-gated ClC-2 chloride channel, in a patient diagnosed with PA at 9 years of age.

ClC-2, the chloride channel encoded by CLCN2, is expressed in many tissues, including brain, kidney, lung and intestine. In addition, CLCN2 RNA is found in the adrenal gland. Immunohistochemistry with an antibody specific for ClC-2 showed intense staining of human adrenal zona glomerulosa, consistent with a role in regulating aldosterone production. Patch-clamp analysis of glomerulosa cells of mouse adrenal gland slices showed hyperpolarization-activated Cl^– currents that were abolished in Clcn2-/- mice. The p.Gly24Asp variant, located in a well-conserved 'inactivation domain', abolished the voltage- and time-dependent gating of ClC-2 and strongly increased Cl^– conductance at resting potentials. Expression of ClC-2^Asp24 in adrenocortical cells increased expression of aldosterone synthase and aldosterone production. The above studies show that a gain-of-function mutation affecting the ClC-2 chloride channel underlies a genetic form of secondary arterial hypertension and identify ClC-2 as the foremost chloride conductor of resting glomerulosa cells. It is likely that the increased Cl^– currents induced by the ClC-2 variants could depolarize the zona glomerulosa cell membrane, thereby opening voltage-gated calcium channels that trigger autonomous aldosterone production by increasing intracellular Ca2+ concentrations. It is also hypothesized that the increased Cl^– currents may overcome the hyperpolarizing currents of K+ channels that normally determine the glomerulosa cell resting potential. These findings implicate the activity of an anion channel in the regulation of aldosterone biosynthesis, PA and hypertension.

1. Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M, Young WF Jr. The management of primary aldosteronism: Case detection, diagnosis, and treatment: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016; 101(5): 1889–1916.

2. Savard S, Amar L, Plouin PF, Steichen O. Cardiovascular complications associated with primary aldosteronism: a controlled cross-sectional study. Hypertension. 2013; 62(2): 331-6.

3. Stowasser M, Gordon RD, Tunny TJ, Klemm SA, Finn WL, Krek AL. Familial hyperaldosteronism type II: five families with a new variety of primary aldosteronism. Clin Exp Pharmacol Physiol. 1992; 19(5): 319-22.