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30.01.2020 | Original Paper

Molecular and Electrophysiological Analyses of ATP2B4 Gene Variants in Bilateral Adrenal Hyperaldosteronism

verfasst von: Namita Ganesh Hattangady, Jessica Foster, Antonio Marcondes Lerario, Daniela Ponce-Balbuena, Juilee Rege, Silvia Monticone, William E. Rainey, Paolo Mulatero, Tobias Else

Erschienen in: Discover Oncology | Ausgabe 1/2020

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Abstract

Primary aldosteronism (PA) is the most common cause of secondary hypertension with a high prevalence among patients with resistant hypertension. Despite the recent discovery of somatic variants in aldosterone-producing adenoma (APA)-associated PA, causes for PA due to bilateral aldosterone production (bilateral hyperaldosteronism; BHA) remain unknown. Herein, we identified rare gene variants in ATP2B4, in a cohort of patients with BHA. ATP2B4 belongs to the same family of Ca-ATPases as ATP2B3, which is involved in the pathogenesis of APA. Endogenous ATP2B4 expression was characterized in adrenal tissue, and the gene variants were functionally analyzed for effects on aldosterone synthase (CYP11B2) expression, steroid production in basal and agonist-stimulated conditions, and for changes in biophysical properties of channel properties. Knockdown of ATP2B4 in HAC15 exhibited reduced angiotensin II stimulation in one of four shRNA clones. Stable HAC15 cell lines with doxycycline (dox) – inducible wild-type and variant forms of ATP2B4 – were generated, and dox-induced upregulation of ATP2B4 mRNA and protein was confirmed. However, ATP2B4 variants did not alter basal or agonist-stimulated CYP11B2 expression. Whole-cell recordings in HAC15 cells indicated robust endogenous ATP2B4 conductance in native cells but reduced conductance with overexpressed WT and variant ATP2B4. The previously defined PA-causing ATP2B3 variant served as a positive control and exhibited elevated CYP11B2 mRNA. In conclusion, while this study did not confirm a pathogenic role for ATP2B4 variants in BHA, we describe the sequencing analysis for familial and sporadic BHA and outline a template for the thorough in vitro characterization of gene variants.

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Titel: Molecular and Electrophysiological Analyses of ATP2B4 Gene Variants in Bilateral Adrenal Hyperaldosteronism
verfasst von: Namita Ganesh Hattangady
Jessica Foster
Antonio Marcondes Lerario
Daniela Ponce-Balbuena
Juilee Rege
Silvia Monticone
William E. Rainey
Paolo Mulatero
Tobias Else
Publikationsdatum: 30.01.2020
Verlag: Springer US
Erschienen in: Discover Oncology / Ausgabe 1/2020
Print ISSN: 1868-8497
Elektronische ISSN: 2730-6011
DOI: https://doi.org/10.1007/s12672-019-00375-0

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25.04.2024 | Nierenkarzinom | Nachrichten

Springer Medizin

Molecular and Electrophysiological Analyses of ATP2B4 Gene Variants in Bilateral Adrenal Hyperaldosteronism

Abstract

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Springer Medizin

Abstract

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