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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 Ca(2+) 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.

Original publication

DOI

10.1016/j.ebiom.2016.10.002

Type

Journal article

Journal

EBioMedicine

Publication Date

11/2016

Volume

13

Pages

225 - 236

Keywords

Adrenal, Aldosterone producing adenoma, Early onset hyperaldosteronism, Familial hyperaldosteronism, Hypertension, Voltage dependent calcium channel, Action Potentials, Adenoma, Adolescent, Adult, Aldosterone, Alleles, Biomarkers, Calcium Channels, T-Type, Cell Line, Child, Child, Preschool, DNA Mutational Analysis, Exome, Female, Gene Expression, Genetic Association Studies, Genotype, High-Throughput Nucleotide Sequencing, Humans, Hyperaldosteronism, Infant, Male, Middle Aged, Mutation, Pedigree, RNA, Messenger, Young Adult