Activating hotspot L205R mutation in PRKACA and adrenal Cushing’s syndrome
Abstract
Adrenal Cushing’s syndrome is caused by excess production of glucocorticoid from adrenocortical tumors and hyperplasias, which leads to metabolic disorders. We performed whole-exome sequencing of 49 blood-tumor pairs and RNA sequencing of 44 tumors from cortisol-producing adrenocortical adenomas (ACAs), adrenocorticotropic hormone–independent macronodular adrenocortical hyperplasias (AIMAHs), and adrenocortical oncocytomas (ADOs). We identified a hotspot in the PRKACA gene with a L205R mutation in 69.2% (27 out of 39) of ACAs and validated in 65.5% of a total of 87 ACAs. Our data revealed that the activating L205R mutation, which locates in the P+1 loop of the protein kinase A (PKA) catalytic subunit, promoted PKA substrate phosphorylation and target gene expression. Moreover, we discovered the recurrently mutated gene DOT1L in AIMAHs and CLASP2 in ADOs. Collectively, these data highlight potentially functional mutated genes in adrenal Cushing’s syndrome.
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Abnormalities in intra-adrenal steroidogenic pathways have been implicated in the development of adrenal tumours.
“abnormalities in intra-adrenal steroidogenic pathways have recently been implicated in the development of adrenal tumours [36].”
From Rapid intra-adrenal feedback regulation of glucocorticoid synthesis (2015) · cites this paper as [36]
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- Authors
- Cao, Y., He, M., Gao, Z., Peng, Y., Li, Y., Li, L., Zhou, W., Li, X., Zhong, X., Lei, Y., Su, T., Wang, H., Jiang, Y., Yang, L., Wei, W., Yang, X., Jiang, X., Liu, L., He, J., Ye, J., Wei, Q., Li, Y., Wang, W., Wang, J., & Ning, G.
- Affiliations
- Shanghai Jiao Tong University (CN)
- BGI Group (China) (CN)
- Corresponding author
- Cao, Yanan
- He, Minghui
- Gao, Zhibo
- Wang, Weiqing
- Wang, Jun
- Ning, Guang
- ORCID
- Venue
- Science
- Published
- 2014-05-23
- Volume
- 344
- Issue
- 6186
- Pages
- 913-917
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2085472231
- Cited by
- 232
- References
- 39
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 15 · 2023: 12 · 2022: 18 · 2021: 16 · 2020: 11 · 2019: 13 · 2018: 14 · 2017: 26 · 2016: 31 · 2015: 33 · 2014: 23
- FWCI
- 37.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Joint Genome Institute
- Topics
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- adrenal Cushing's syndrome, PRKACA, protein kinase A, adrenal adenoma, adrenocortical oncocytoma, DOT1L, CLASP2, mutational hotspots
- MeSH terms
- Adrenal Cortex Neoplasms, Arginine, Cells, Cultured, Cushing Syndrome, Glucocorticoids, Humans, Hydrocortisone, Leucine, Methyltransferases, Microtubule-Associated Proteins, Mutation, Histone-Lysine N-Methyltransferase, Adrenocortical Adenoma, Amino Acid Substitution, Catalytic Domain, Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
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