CACNA1H Mutations Are Associated With Different Forms of Primary Aldosteronism

EBioMedicine. 2016 Nov;13:225-236. doi: 10.1016/j.ebiom.2016.10.002.

Georgios Daniil ¹, Fabio L Fernandes-Rosa ², Jean Chemin ³, Iulia Blesneac ³, Jacques Beltrand ⁴, Michel Polak ⁴, Xavier Jeunemaitre ⁵, Sheerazed Boulkroun ¹, Laurence Amar ⁶, Tim M Strom ⁷, Philippe Lory ³, Maria-Christina Zennaro ⁸

Affiliations

1 INSERM, UMRS_970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
2 INSERM, UMRS_970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France. Electronic address: [email protected].
3 Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS UMR 5203, INSERM U 1191, Montpellier F-34094, France; LabEx Ion Channel Science and Therapeutics, Montpellier F-34094, France.
4 Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, Service d'Endocrinologie, Paris, France; Inserm UMR_1016, Institut Cochin, Paris, France; Institut Imagine, Paris Descartes - Université Sorbonne Paris Cité, Paris, France.
5 INSERM, UMRS_970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France.
6 INSERM, UMRS_970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Unité Hypertension artérielle, Paris, France.
7 Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany.
8 INSERM, UMRS_970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France. Electronic address: [email protected].

PMID: 27729216 DOI: 10.1016/j.ebiom.2016.10.002

Abstract

Primary aldosteronism (PA) is the most common form of secondary hypertension. Mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D are found in aldosterone producing adenoma (APA) and familial hyperaldosteronism (FH). A recurrent mutation in CACNA1H (coding for Cav3.2) was identified in a familial form of early onset PA. Here we performed whole exome sequencing (WES) in patients with different types of PA to identify new susceptibility genes. Four different heterozygous germline CACNA1H variants were identified. A de novo Cav3.2 p.Met1549Ile variant was found in early onset PA and multiplex developmental disorder. Cav3.2 p.Ser196Leu and p.Pro2083Leu were found in two patients with FH, and p.Val1951Glu was identified in one patient with APA. Electrophysiological analysis of mutant Cav3.2 channels revealed significant changes in the Ca²⁺ current properties for all mutants, suggesting a gain of function phenotype. Transfections of mutant Cav3.2 in H295R-S2 cells led to increased aldosterone production and/or expression of genes coding for steroidogenic enzymes after K⁺ stimulation. Identification of CACNA1H mutations associated with early onset PA, FH, and APA suggests that CACNA1H might be a susceptibility gene predisposing to PA with different phenotypic presentations, opening new perspectives for genetic diagnosis and management of patients with PA.

Keywords

Adrenal; Aldosterone producing adenoma; Early onset hyperaldosteronism; Familial hyperaldosteronism; Hypertension; Voltage dependent calcium channel.

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