Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism
Open accessAbstract
Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel gene KCNJ5 that result in cell depolarization and Ca(2+) influx cause ∼40% of these tumors. We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5. The altered residues lie in the S6 segments that line the channel pore. Both alterations result in channel activation at less depolarized potentials; Gly403 alterations also impair channel inactivation. These effects are inferred to cause increased Ca(2+) influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa. We also identified de novo germline mutations at identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain-of-function Ca(2+) channel mutations in APAs and primary aldosteronism.
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CACNA1D is highly expressed in the adrenal glands, and when mutated gives rise to cerebral palsy/motor disorders; it has been linked to auditory processing and is among the positively selected genes in some vocal learners.
“It is highly expressed in the adrenal glands [90], and, when mutated, gives rise to cerebral palsy/motor disorders [91]. It has been linked to auditory processing [92], and said to be among the positively selected genes in some vocal learners [93].”
From Self-domestication in Homo sapiens: Insights from comparative genomics (2017) · cites this paper as [91]
Somatic driver mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 have been discovered in aldosterone-producing adenoma tissue, altogether accounting for most cases.
“Similarly, somatic driver mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 have been discovered in APA tissue, altogether accounting for most cases (157, 158, 161–164).”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [158]
Rare familial forms of primary aldosteronism are associated with germline mutations in KCNJ5, CACNA1D, CACNA1H, and CLCN2.
“Rare familial forms of PA have been shown to be associated with germline mutations in KCNJ5 (157), CACNA1D (158), CACNA1H (159), and CLCN2 (160).”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [158]
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- Authors
- Scholl, U. I., Goh, G., Stölting, G., de Oliveira, R. C., Choi, M., Overton, J. D., Fonseca, A. L., Korah, R., Starker, L. F., Kunstman, J. W., Prasad, M. L., Hartung, E. A., Mauras, N., Benson, M. R., Brady, T., Shapiro, J. R., Loring, E., Nelson-Williams, C., Libutti, S. K., Mane, S., Hellman, P., Westin, G., Åkerström, G., Björklund, P., Carling, T., Fahlke, C., Hidalgo, P., & Lifton, R. P.
- Affiliations
- Yale University (US)
- Howard Hughes Medical Institute (US)
- Forschungszentrum Jülich (DE)
- Uppsala University (SE)
- Children's Hospital of Philadelphia (US)
- Nemours Children's Clinic (US)
- Johns Hopkins University (US)
- Kennedy Krieger Institute (US)
- Albert Einstein College of Medicine (US)
- Yale Cancer Center (US)
- Corresponding author
- Lifton, Richard P
- ORCID
- Scholl, Ute I
- Goh, Gerald
- Stölting, Gabriel
- Choi, Murim
- Overton, John D
- Fonseca, Annabelle L
- Kunstman, John W
- Prasad, Manju L
- Hartung, Erum A
- Mauras, Nelly
- Benson, Matthew R
- Brady, Tammy
- Shapiro, Jay R
- Nelson-Williams, Carol
- Libutti, Steven K
- Mane, Shrikant
- Hellman, Per
- Westin, Gunnar
- Björklund, Peyman
- Carling, Tobias
- Fahlke, Christoph
- Hidalgo, Patricia
- Lifton, Richard P
- Venue
- Nature Genetics
- Published
- 2013-08-04
- Volume
- 45
- Issue
- 9
- Pages
- 1050-1054
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3876926
- OpenAlex
- W1967440935
- Cited by
- 627
- References
- 28
- Citations by year
- 2026: 34 · 2025: 31 · 2024: 38 · 2023: 52 · 2022: 45 · 2021: 48 · 2020: 53 · 2019: 51 · 2018: 48 · 2017: 49 · 2016: 66 · 2015: 59 · 2014: 40 · 2013: 10
- FWCI
- 45.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Human Genome Research Institute (U54HG006504)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK079310)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- CACNA1D, voltage-gated calcium channels, aldosterone-producing adenoma, primary aldosteronism, somatic mutations, germline mutations, gain-of-function mutations, calcium influx, KCNJ5, channel inactivation, neuromuscular abnormalities, hypertension, adrenal glomerulosa
- MeSH terms
- Adrenal Cortex Neoplasms, Aldosterone, Amino Acid Sequence, Cell Line, Child, Child, Preschool, Female, Humans, Hyperaldosteronism, Male, Molecular Sequence Data, Mutation, Pedigree, Protein Conformation, Sequence Alignment, Germ-Line Mutation, Adrenocortical Adenoma, Calcium Channels, L-Type
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