title: An update on novel mechanisms of primary aldosteronism.
abstract: Primary aldosteronism (PA) is the most common and curable form of secondary hypertension. It is caused in the majority of cases by either unilateral aldosterone overproduction due to an aldosterone-producing adenoma (APA) or by bilateral adrenal hyperplasia. Recent advances in genome technology have allowed researchers to unravel part of the genetic abnormalities underlying the development of APA and familial hyperaldosteronism. Recurrent somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and ATPases (ATP1A1 and ATP2B3) regulating intracellular ionic homeostasis and cell membrane potential have been identified in APA. Similar germline mutations of KCNJ5 were identified in a severe familial form of PA, familial hyperaldosteronism type 3 (FH3), whereas de novo germline CACNA1D mutations were found in two cases of hyperaldosteronism associated with a complex neurological disorder. These results have allowed a pathophysiological model of APA development to be established. This model involves modifications in intracellular ionic homeostasis and membrane potential, accounting for ∼50% of all tumors, associated with specific gender differences and severity of PA. In this review, we describe the different genetic abnormalities associated with PA and discuss the mechanisms whereby they lead to increased aldosterone production and cell proliferation. We also address some of the foreseeable consequences that genetic knowledge may contribute to improve diagnosis and patient care.
authors.affiliation: INSERMUMRS_970, Paris Cardiovascular Research Center - PARCC, 56, rue Leblanc, 75015 Paris, FranceUniversity Paris DescartesSorbonne Paris Cité, Paris, FranceAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, Paris, France INSERMUMRS_970, Paris Cardiovascular Research Center - PARCC, 56, rue Leblanc, 75015 Paris, FranceUniversity Paris DescartesSorbonne Paris Cité, Paris, FranceAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, Paris, France INSERMUMRS_970, Paris Cardiovascular Research Center - PARCC, 56, rue Leblanc, 75015 Paris, FranceUniversity Paris DescartesSorbonne Paris Cité, Paris, FranceAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, Paris, France maria-christina.zennaro@inserm.fr.
authors.forename: Maria-Christina
authors.initials: MC
authors.lastname: Zennaro
authors.affiliation: INSERMUMRS_970, Paris Cardiovascular Research Center - PARCC, 56, rue Leblanc, 75015 Paris, FranceUniversity Paris DescartesSorbonne Paris Cité, Paris, FranceAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, Paris, France INSERMUMRS_970, Paris Cardiovascular Research Center - PARCC, 56, rue Leblanc, 75015 Paris, FranceUniversity Paris DescartesSorbonne Paris Cité, Paris, FranceAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, Paris, France.
authors.forename: Sheerazed
authors.initials: S
authors.lastname: Boulkroun
authors.affiliation: INSERMUMRS_970, Paris Cardiovascular Research Center - PARCC, 56, rue Leblanc, 75015 Paris, FranceUniversity Paris DescartesSorbonne Paris Cité, Paris, FranceAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, Paris, France INSERMUMRS_970, Paris Cardiovascular Research Center - PARCC, 56, rue Leblanc, 75015 Paris, FranceUniversity Paris DescartesSorbonne Paris Cité, Paris, FranceAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, Paris, France INSERMUMRS_970, Paris Cardiovascular Research Center - PARCC, 56, rue Leblanc, 75015 Paris, FranceUniversity Paris DescartesSorbonne Paris Cité, Paris, FranceAssistance Publique-Hôpitaux de ParisHôpital Européen Georges Pompidou, Service de Génétique, Paris, France.
authors.forename: Fabio
authors.initials: F
authors.lastname: Fernandes-Rosa
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics / Q000378:metabolism; D018246:Adrenocortical Adenoma / Q000235:genetics / Q000378:metabolism; D000450:Aldosterone / Q000235:genetics / Q000378:metabolism; D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D006929:Hyperaldosteronism / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D009384:Paraneoplastic Endocrine Syndromes / Q000235:genetics
chemical_list: C472073:CACNA1D protein, human; D020746:Calcium Channels, L-Type; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; D000450:Aldosterone
keywords: ATPase; aldosterone producing adenoma; bilateral adrenal hyperplasia; calcium channels; endocrine tumor; genetic susceptibility; genotype-phenotype correlation; phenotypic variability; potassium channels; primary aldosteronism; somatic mutations