Molecular Genetics of Hyperaldosteronism

Abstract

Abstract 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.