Recurrent somatic mutations underlie corticotropin-independent Cushing’s syndrome
Abstract
Cushing’s syndrome is caused by excess cortisol production from the adrenocortical gland. In corticotropin-independent Cushing’s syndrome, the excess cortisol production is primarily attributed to an adrenocortical adenoma, in which the underlying molecular pathogenesis has been poorly understood. We report a hotspot mutation (L206R) in PRKACA , which encodes the catalytic subunit of cyclic adenosine monophosphate (cAMP)–dependent protein kinase (PKA), in more than 50% of cases with adrenocortical adenomas associated with corticotropin-independent Cushing’s syndrome. The L206R PRKACA mutant abolished its binding to the regulatory subunit of PKA (PRKAR1A) that inhibits catalytic activity of PRKACA, leading to constitutive, cAMP-independent PKA activation. These results highlight the major role of cAMP-independent activation of cAMP/PKA signaling by somatic mutations in corticotropin-independent Cushing’s syndrome, providing insights into the diagnosis and therapeutics of this syndrome.
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Somatic activating mutations of GNAS occur in 5% to 17% of cortisol-secreting adrenal adenomas.
“Somatic activating mutations of GNAS, which encodes the α-subunit of the stimulatory G protein (GSα), occur in 5% to 17% of adrenal adenomas which are cortisol secreting (142,143).”
From Adrenal incidentaloma (2020) · cites this paper as [142]
Somatic activating mutations of PRKACA are implicated in up to 50% of patients with adenomas with clinical Cushing's syndrome, but not in adenomas producing less cortisol.
“Somatic activating mutations of protein kinase A catalytic subunit (PRKACA) has been implicated in up to 50% of patients with adenomas with clinical Cushing’s syndrome, but not in adenomas producing less cortisol (138,142,147).”
From Adrenal incidentaloma (2020) · cites this paper as [142]
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References 27 · Cited by 209
- Authors
- Sato, Y., Maekawa, S., Ishii, R., Sanada, M., Morikawa, T., Shiraishi, Y., Yoshida, K., Nagata, Y., Sato-Otsubo, A., Yoshizato, T., Suzuki, H., Shiozawa, Y., Kataoka, K., Kon, A., Aoki, K., Chiba, K., Tanaka, H., Kume, H., Miyano, S., Fukayama, M., Nureki, O., Homma, Y., & Ogawa, S.
- Affiliations
- Kyoto University (JP)
- The University of Tokyo (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
- Corresponding author
- Sato, Yusuke
- Maekawa, Shigekatsu
- Homma, Yukio
- Ogawa, Seishi
- ORCID
- Sato, Yusuke
- Maekawa, Shigekatsu
- Ishii, Ryohei
- Sanada, Masashi
- Morikawa, Teppei
- Shiraishi, Yuichi
- Yoshida, Kenichi
- Nagata, Yasunobu
- Yoshizato, Tetsuichi
- Suzuki, Hiromichi
- Shiozawa, Yusuke
- Kataoka, Keisuke
- Kon, Ayana
- Aoki, Kosuke
- Chiba, Kenichi
- Tanaka, Hiroko
- Kume, Haruki
- Miyano, Satoru
- Fukayama, Masashi
- Nureki, Osamu
- Homma, Yukio
- Ogawa, Seishi
- Venue
- Science
- Published
- 2014-05-23
- Volume
- 344
- Issue
- 6186
- Pages
- 917-920
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W1992384218
- Semantic Scholar
- 2e9218441f66e204e7e54754945806d8a10eebc7
- Cited by
- 209
- References
- 27
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 15 · 2023: 6 · 2022: 21 · 2021: 12 · 2020: 10 · 2019: 12 · 2018: 17 · 2017: 19 · 2016: 35 · 2015: 30 · 2014: 15
- FWCI
- 32.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- adrenal adenoma, PRKACA, protein kinase A, PRKAR1A, somatic mutations
- MeSH terms
- Adrenal Cortex Neoplasms, Adrenocorticotropic Hormone, Animals, Cushing Syndrome, DNA Mutational Analysis, Humans, Mutation, PC12 Cells, Adrenocortical Adenoma, Catalytic Domain, NIH 3T3 Cells, GTP-Binding Protein alpha Subunits, Mice, Rats, Cyclic AMP-Dependent Protein Kinase Catalytic Subunits, HEK293 Cells
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