Molecular Genetics of Hyperaldosteronism


In primary aldosteronism, the adrenal gland produces excessive amounts of the steroid hormone aldosterone, which causes hypertension. Common causes are aldosterone‐producing adenomas (benign tumours) and bilateral adrenal hyperplasia. The majority of aldosterone‐producing adenomas carry somatic mutations in known disease genes. These include KCNJ5 (a potassium channel), CACNA1D (a calcium channel) and ATP1A1 and AT2B3 (ATPase subunits). These mutations either directly or indirectly cause increased intracellular calcium levels, which lead to increased aldosterone production and proliferation. Mutations in CTNNB1 (beta‐catenin) are rare. The molecular mechanisms underlying bilateral adrenal hyperplasia are largely unknown, with the exception of rare forms of familial hyperaldosteronism (FH). FH‐I, ‐III and ‐IV are caused by germ line mutations in CYP11B2 (aldosterone synthase), KCNJ5 and CACNA1H (another calcium channel), respectively, and a syndrome that includes neurologic abnormalities is due to germ line mutations in CACNA1D. These observations suggest pathways for the development of novel diagnostic and therapeutic strategies in primary aldosteronism.

Key Concepts

  • Primary aldosteronism is the most common cause of secondary hypertension, caused by aldosterone‐producing adenoma or bilateral adrenal hyperplasia.
  • Recent exome sequencing studies have identified the genetic basis of the majority of aldosterone‐producing adenomas.
  • Somatic mutations in the potassium channel KCNJ5 explain about 40% of aldosterone‐producing adenomas.
  • Mutations in KCNJ5 are associated with female gender, early onset and larger tumour size.
  • Other somatic mutations in aldosterone‐producing adenomas affect the CACNA1D, ATP1A1, ATP2B3 and CTNNB1 genes.
  • The shared common final pathway of somatic mutations in aldosterone‐producing adenomas is increased calcium signalling, which causes excessive aldosterone production and proliferation.
  • The pathophysiology of sporadic bilateral adrenal hyperplasia is largely unknown.
  • Rare forms of familial hyperaldosteronism (FH) include FH‐I, ‐III and ‐IV, caused by germ line mutations in CYP11B2, KCNJ5 and CACNA1H, respectively, and FH‐II, whose genetic basis remains unknown.
  • The identification of the molecular mechanisms of primary aldosteronism suggests pathways for the development of novel diagnostic and therapeutic strategies.

Keywords: KCNJ5; CACNA1D; ATP1A1; ATP2B2; CACNA1H; CYP11B2; exome sequencing; calcium; ion channel; hypertension

Figure 1. Regulation of aldosterone production. ACE, angiotensin‐converting enzyme.
Figure 2. Cellular regulation of aldosterone production. (a) Glomerulosa cell in the absence of stimulatory factors. The resting membrane potential is hyperpolarised, voltage‐gated calcium channels remain closed and aldosterone production is suppressed. (b) Binding of angiotensin II to its receptor leads to depolarisation and activation of voltage‐gated calcium channels and release of calcium from intracellular stores via phospholipase C (PLC) and inositol trisphosphate (IP3). Hyperkalaemia directly causes depolarisation and activation of voltage‐gated calcium channels. Intracellular calcium leads to increased CYP11B2 (aldosterone synthase) transcription via Ca2+/calmodulin‐dependent protein kinase (CAMK).
Figure 3. Mechanism of mutations in primary aldosteronism. (a) Activation of aldosterone production by ion channel and pump mutations. ATPase mutations cause abnormal Na+ or H+ permeability, KCNJ5 mutations lead to abnormal Na+ permeability, and calcium channel mutations (CACNA1D, CACNA1H) cause increased calcium influx. All lead to increased calcium signalling and activation of CYP11B2 (aldosterone synthase) transcription. (b) In FH‐I, the chimaeric gene that arises from crossover between CYP11B1 and CYP11B2 is activated by ACTH.


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Further Reading

Dutta RK, Soderkvist P and Gimm O (2016) Genetics of primary hyperaldosteronism. Endocrine‐Related Cancer 23 (10): R437–R454.

Korah HE and Scholl UI (2015) An update on familial Hyperaldosteronism. Hormone and Metabolic Research 47 (13): 941–946.

Lenzini L and Rossi GP (2015) The molecular basis of primary aldosteronism: from chimeric gene to channelopathy. Current Opinion in Pharmacology 21: 35–42.

Padmanabhan S, Caulfield M and Dominiczak AF (2015) Genetic and molecular aspects of hypertension. Circulation Research 116 (6): 937–959.

Spat A and Hunyady L (2004) Control of aldosterone secretion: a model for convergence in cellular signaling pathways. Physiological Reviews 84 (2): 489–539.

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Scholl, Ute I(Jul 2017) Molecular Genetics of Hyperaldosteronism. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027250]