Overview of the genetic determinants of primary aldosteronism

Abstract

Primary aldosteronism is the most common cause of secondary hypertension. The syndrome accounts for 10% of all cases of hypertension and is primarily caused by bilateral adrenal hyperplasia or aldosterone-producing adenoma. Over the last few years, the use of exome sequencing has significantly improved our understanding of this syndrome. Somatic mutations in the KCNJ5, ATP1A1, ATP2B3 or CACNA1D genes are present in more than half of all cases of aldosterone-producing adenoma (~40%, ~6%, ~1% and ~8%, respectively). Germline gain-of-function mutations in KCNJ5 are now known to cause familial hyperaldosteronism type III, and an additional form of genetic hyperaldosteronism has been reported in patients with germline mutations in CACNA1D. These genes code for channels that control ion homeostasis across the plasma membrane of zona glomerulosa cells. Moreover, all these mutations modulate the same pathway, in which elevated intracellular calcium levels lead to aldosterone hyperproduction and (in some cases) adrenal cell proliferation. From a clinical standpoint, the discovery of these mutations has potential implications for patient management. The mutated channels could be targeted by drugs, in order to control hormonal and overgrowth-related manifestations. Furthermore, some of these mutations are associated with high cell turnover and may be amenable to diagnosis via the sequencing of cell-free (circulating) DNA. However, genotype-phenotype correlations in patients harboring these mutations have yet to be characterized. Despite this recent progress, much remains to be done to elucidate the yet unknown mechanisms underlying sporadic bilateral adrenal hyperplasia.

Keywords: potassium channels; primary aldosteronism; secondary hypertension.

Figure 1

A simplified, schematic diagram of ZG cells at rest, when the cells are hyperpolarized due to leaky K⁺ channels (TASK). Na⁺/K⁺ ATPase and Kir3.4 contribute to the maintenance of membrane hyperpolarization. The voltage-gated Ca²⁺ channels are closed. Abbreviations: CYP11B2, aldosterone synthase; TASK, TWIK-related acid sensitive K channels; Kir3.4, inwardly rectifying potassium channel Kir3.4; AT1R, type 1 angiotensin II receptor; Ca_v 3.x, low-voltage activated calcium channels; Ca_v 1.x, high-voltage activated calcium channels; MC2R, ACTH receptor; ACTH, adrenocorticotropic hormone; ZG, zona glomerulosa.

Figure 2

Regulation of aldosterone secretion in the physiologic state. Binding of angiotensin II to the AT1R blocks Kir3.4 potassium channels, TASK and Na⁺/K⁺ ATPase (1), this depolarizes the membrane (2) and results in the opening of voltage-gated Ca²⁺ channels (3). The resulting increase in intracellular levels provides the signal for increased expression of aldosterone synthase (4) through many different actions (including increased transcription of steroidogenic acute regulator protein). Abbreviations: CYP11B2, aldosterone synthase; TASK, TWIK-related acid sensitive K channels; Kir3.4, inwardly rectifying potassium channel Kir3.4; AT1R, type 1 angiotensin II receptor; ATII, angiotensin II; Ca_v 3.x, low-voltage activated calcium channels; Ca_v 1.x, high-voltage activated calcium channels; MC2R, ACTH receptor; ACTH, adrenocorticotropic hormone; StAR, steroidogenic acute regulator protein.

Figure 3

The mechanism thought to underlie hyperaldosteronism in patients with KCNJ5 mutations that cause Kir3.4 to lose its potassium selectivity. The mutated channels allow sodium entry, which triggers depolarization. Abbreviations: CYP11B2, aldosterone synthase; TASK, TWIK-related acid sensitive K channels; Kir3.4, inwardly rectifying potassium channel Kir3.4; AT1R, type 1 angiotensin II receptor; Ca_v 3.x, low-voltage activated calcium channels; Ca_v 1.x, high-voltage activated calcium channels; MC2R, ACTH receptor; ACTH, adrenocorticotropic hormone.

Figure 4

A schematic diagram of the structure of Na⁺/K⁺ ATPase subunit alpha 1 (upper panel, ATP1A1), Ca²⁺ ATPase 3 (middle panel, ATP2B3) and the alpha subunit of low-voltage activated calcium channel Ca_v1.3, with known mutations indicated by red circles (lower panel). Notes: Upper and middle panels adapted by permission from Macmillan Publishers Ltd: Nature Genetics, Beuschlein F, Boulkroun S, Osswald A, et al. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat Genet. 2013;45(4):440–444, 444e1–2. Copyright © 2013. Lower panel adapted by permission from Macmillan Publishers Ltd: Nature Genetics, Azizan EA, Poulsen H, Tuluc P, et al. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet. 2013;45(9):1055–1060. Copyright © 2013.

Figure 5

The molecular mechanism thought to underlie hyperaldosteronism in patients with ATP1A1 mutations. The Na⁺/K⁺ ATPase changes from actively pumping (three Na⁺ outwards and two K⁺ inwards) to passive conduction of an inward current (protons or Na⁺ ions, depending on the mutation). Abbreviations: CYP11B2, aldosterone synthase; TASK, TWIK-related acid sensitive K channels; Kir3.4, inwardly rectifying potassium channel Kir3.4; AT1R, type 1 angiotensin II receptor; H⁺, proton; Ca_v 3.x, low-voltage activated calcium channels; Ca_v 1.x, high-voltage activated calcium channels; MC2R, ACTH receptor; ACTH, adrenocorticotropic hormone.

Figure 6

The molecular mechanism thought to underlie GRA. Unequal crossing-over between the 11 β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes results in a chimeric gene and the control of aldosterone secretion by ACTH. Abbreviations: TASK, TWIK-related acid sensitive K channels; Kir3.4, inwardly rectifying potassium channel Kir3.4; AT1R, type 1 angiotensin II receptor; Ca_v 3.x, low-voltage activated calcium channels; Ca_v 1.x, high-voltage activated calcium channels; MC2R, ACTH receptor; ACTH, adrenocorticotropic hormone.