title: Genetics of mineralocorticoid excess: an update for clinicians.
abstract: Aldosterone plays a major role in the regulation of sodium and potassium homeostasis and blood pressure. More recently, aldosterone has emerged as a key hormone mediating end organ damage. In extreme cases, dysregulated aldosterone production leads to primary aldosteronism (PA), the most common form of secondary hypertension. However, even within the physiological range, high levels of aldosterone are associated with an increased risk of developing hypertension over time. PA represents the most common and curable form of hypertension, with a prevalence that increases with the severity of hypertension. Although genetic causes underlying glucocorticoid-remediable aldosteronism, one of the three Mendelian forms of PA, were established some time ago, somatic and inherited mutations in the potassium channel GIRK4 have only recently been implicated in the formation of aldosterone-producing adenoma (APA) and in familial hyperaldosteronism type 3. Moreover, recent findings have shown somatic mutations in two additional genes, involved in maintaining intracellular ionic homeostasis and cell membrane potential, in a subset of APAs. This review summarizes our current knowledge on the genetic determinants that contribute to variations in plasma aldosterone and renin levels in the general population and the genetics of familial and sporadic PA. Various animal models that have significantly improved our understanding of the pathophysiology of excess aldosterone production are also discussed. Finally, we outline the cardiovascular, renal, and metabolic consequences of mineralocorticoid excess beyond blood pressure regulation.
authors.affiliation: INSERM, UMRS_970, Paris Cardiovascular Research Center, 56 Rue Leblanc, 75015 Paris, France.
authors.forename: Maria-Christina
authors.initials: MC
authors.lastname: Zennaro
authors.forename: Amanda Jane
authors.initials: AJ
authors.lastname: Rickard
authors.forename: Sheerazed
authors.initials: S
authors.lastname: Boulkroun
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000378:metabolism; D018246:Adrenocortical Adenoma / Q000378:metabolism; D000450:Aldosterone / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics*; D006801:Humans; D006929:Hyperaldosteronism / Q000097:blood / Q000150:complications* / Q000235:genetics* / Q000378:metabolism; D006973:Hypertension / Q000097:blood / Q000209:etiology* / Q000235:genetics; D008901:Mineralocorticoids / Q000235:genetics; D009154:Mutation; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics; D012083:Renin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; D008901:Mineralocorticoids; D000450:Aldosterone; D012083:Renin; C499076:ATP1A1 protein, human; D053499:Plasma Membrane Calcium-Transporting ATPases; C506962:ATP2B3 protein, human; D000254:Sodium-Potassium-Exchanging ATPase