title: CACNA1H Mutations Are Associated With Different Forms of Primary Aldosteronism.
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.
authors.affiliation: INSERM, UMRS_970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Georgios
authors.initials: G
authors.lastname: Daniil
authors.affiliation: 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: fabio.fernandes-rosa@inserm.fr.
authors.forename: Fabio L
authors.initials: FL
authors.lastname: Fernandes-Rosa
authors.affiliation: 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.
authors.forename: Jean
authors.initials: J
authors.lastname: Chemin
authors.affiliation: 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.
authors.forename: Iulia
authors.initials: I
authors.lastname: Blesneac
authors.affiliation: 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.
authors.forename: Jacques
authors.initials: J
authors.lastname: Beltrand
authors.affiliation: 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.
authors.forename: Michel
authors.initials: M
authors.lastname: Polak
authors.affiliation: 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.
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.affiliation: INSERM, UMRS_970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Sheerazed
authors.initials: S
authors.lastname: Boulkroun
authors.affiliation: 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.
authors.forename: Laurence
authors.initials: L
authors.lastname: Amar
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: 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.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lory
authors.affiliation: 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: maria-christina.zennaro@inserm.fr.
authors.forename: Maria-Christina
authors.initials: MC
authors.lastname: Zennaro
mesh_terms: D000200:Action Potentials; D000236:Adenoma / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000450:Aldosterone / Q000096:biosynthesis; D000483:Alleles; D015415:Biomarkers; D020747:Calcium Channels, T-Type / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006929:Hyperaldosteronism / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics; D055815:Young Adult
chemical_list: D015415:Biomarkers; C479952:CACNA1H protein, human; D020747:Calcium Channels, T-Type; D012333:RNA, Messenger; D000450:Aldosterone
keywords: Adrenal; Aldosterone producing adenoma; Early onset hyperaldosteronism; Familial hyperaldosteronism; Hypertension; Voltage dependent calcium channel