Genetics of primary hyperaldosteronism

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   Figure 1

   The renin–angiotensin system and aldosterone production under normal physiologic conditions. The liver continously produces angiotensinogen that is released into the plasma. When the blood pressure and volume decreases, the kidney granular cells start to produce renin, which cleaves angiotensinogen into angiotensin I. Angiotensin I is subsequently cleaved into angiotensin II, which binds to angiotensin II binding receptors (AT_1A, AT_1B and AT₂) on zona glomerulosa cells of the adrenal cortex. This triggers the production of aldosterone. Aldosterone binds to the mineralocorticoid receptor in the kidney. ACE, angiotensinogen.
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   Figure 2

   Showing one subunit of the Kir3.4 channel. Red circles indicate the most frequently found somatic and germline mutations in aldosterone-producing adenomas.
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   Figure 3

   Illustrating the structure of Na⁺/K⁺ ATPase subunit α1. Red circles indicate the mutations found in ATP1A1 in sporadic aldosterone-producing adenomas. All mutations are located in the second and fourth transmembrane domain of ATP1A1.
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   Figure 4

   Illustrating the structure of the Ca²⁺ ATPase 3 subunit. Red circles indicate the mutations found in ATP2B3 in sporadic aldosterone-producing adenomas. All mutations are located in the fourth transmembrane domain of ATP2B3. This is the Ca²⁺ binding site.
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   Figure 5

   Showing the structure of the alpha subunit of Ca_v1.3 channel. Red and black circles indicate the mutations found in CACNA1D and CACNA1H, respectively, in sporadic aldosterone-producing adenomas. CACNA1D mutations are distributed throughout the protein.
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   Figure 6

   The Wnt/β-catenin signaling pathway is involved in the formation of sporadic APA. Wnt ligands bind to frizzled (Fz) and its coreceptor, LRP5/6, to inhibit the degradation of β-catenin. The stabilized β-catenin translocates into the nucleus, which results in enhanced expression of the transcription factor TCF/LEF1 and ultimately leads to the expression of target genes. In aldosterone-producing adenomas, TCF/LEF1 binds to NURR1/NUR77, which is a trancription factor of CYP11B2.
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   Figure 7

   Structure of β-catenin. Glycogen synthase kinase 3 (GSK3) phosphorylate the serines (colored) in the GSK3β binding domain of β-catenin. The mutations are localized to the phosphorylation sites and indicated with red circles.
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   Figure 8

   Structure of ARMC5. The red circles indicate mutations found in ARMC5 of patients with APA. Mutations are distributed throughout the protein.
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   Figure 9

   Pathways and channels involved in the biosynthesis of aldosterone. Under physiological conditions, binding of angiotensin II on angiotensin receptor type I (AT1R) activates the voltage-gated Ca²⁺ channels, which results into influx of Ca²⁺ ions. AT1R also elicit inositol 1,4,5-trisphosphate receptors (IP3Rs) to release Ca²⁺ release from the endoplasmic reticulum. Under pathological conditions, genes coding for Na⁺/K⁺-ATPase, the potassium channels KCNJ5 or the Ca²⁺ ATPase and Ca²⁺ channel CACNA1D are mutated, leading to membrane depolarization and influx of calcium through voltage-gated calcium channel. Mutations in ATP2B3 affect the recycling of Ca²⁺. However, mutations in L-type Ca²⁺ channel CACNA1D lead to early opening at lower potential and a sustained activation of the channel, which increases the calcium influx. An increase in the intracellular calcium concentration is found to trigger the production of aldosterone.

• © 2016 Society for Endocrinology