Abstract/Summary:

Driver somatic mutations for aldosterone excess have been found in ≈90% of aldosterone-producing adenomas (APAs) using an aldosterone synthase (CYP11B2)-guided sequencing approach. In the present study, we identified a novel somatic CACNA1H mutation (c.T4289C, p.I1430T) in an APA without any currently known aldosterone-driver mutations using CYP11B2 immunohistochemistry-guided whole exome sequencing. The CACNA1H gene encodes a voltage-dependent T-type calcium channel alpha-1H subunit. Germline variants in this gene are known as a cause of familial hyperaldosteronism IV. Targeted next-generation sequencing detected identical CACNA1H variants in 2 additional APAs in a cohort of the University of Michigan, resulting in a prevalence of 4% (3/75) in APAs. We tested the functional effect of the variant on adrenal cell aldosterone production and CYP11B2 mRNA expression using the human adrenocortical HAC15 cell line with a doxycycline-inducible CACNA1HI1430T mutation. Doxycycline treatment increased CYP11B2 mRNA levels as well as aldosterone production, supporting a pathological role of the CACNA1H p.I1430T mutation on the development of primary aldosteronism. In conclusion, somatic CACNA1H mutation is a genetic cause of APAs. Although the prevalence of this mutation is low, this study will provide better understanding of molecular mechanism of inappropriate aldosterone production in APAs.

Authors: Kazutaka Nanba, Amy R. Blinder, Juilee Rege, Namita G. Hattangady, Tobias Else, Chia-Jen Liu, Scott A. Tomlins, Pankaj Vats, Chandan Kumar-Sinha, Thomas J. Giordano, William E. Rainey
Keywords: calcium channel mutations, aldosterone, aldosterone-producing adenomas (APAs)
DOI Number: 10.1161/HYPERTENSIONAHA.119.14349      Publication Year: 2020

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©2021 Primary Aldosteronism Foundation

The Primary Aldosteronism Foundation is a registered 501(c)(3) public charity. Donations are tax deductible in the US.