Back to Search
Start Over
Somatic CACNA1H Mutation As a Cause of Aldosterone-Producing Adenoma.
- Source :
-
Hypertension (Dallas, Tex. : 1979) [Hypertension] 2020 Mar; Vol. 75 (3), pp. 645-649. Date of Electronic Publication: 2020 Jan 27. - Publication Year :
- 2020
-
Abstract
- 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 CACNA1H <superscript> I1430T </superscript> 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.
- Subjects :
- Adenoma complications
Adenoma metabolism
Adrenal Cortex Neoplasms complications
Adrenal Cortex Neoplasms metabolism
Angiotensin II pharmacology
Calcium Signaling
Cell Line, Tumor
Cytochrome P-450 CYP11B2 biosynthesis
Cytochrome P-450 CYP11B2 genetics
Doxycycline pharmacology
Enzyme Induction drug effects
Genetic Vectors drug effects
High-Throughput Nucleotide Sequencing
Humans
Lentivirus genetics
Mutation, Missense
RNA, Messenger biosynthesis
RNA, Messenger genetics
RNA, Neoplasm biosynthesis
RNA, Neoplasm genetics
Recombinant Proteins biosynthesis
Recombinant Proteins genetics
Exome Sequencing
Adenoma genetics
Adrenal Cortex Neoplasms genetics
Aldosterone biosynthesis
Calcium Channels, T-Type genetics
Hyperaldosteronism etiology
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4563
- Volume :
- 75
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Hypertension (Dallas, Tex. : 1979)
- Publication Type :
- Academic Journal
- Accession number :
- 31983310
- Full Text :
- https://doi.org/10.1161/HYPERTENSIONAHA.119.14349