Novel somatic mutations in the catalytic subunit of the protein kinase A as a cause of adrenal Cushing’s syndrome: a European multicentric study
Abstract
CONTEXT: Somatic mutations in PRKACA gene, encoding the catalytic subunit of protein kinase A (PKA), have been recently found in a high proportion of sporadic adenomas associated with Cushing's syndrome. The aim was to analyze the PRKACA mutation in a large cohort of patients with adrenocortical masses. METHODS: Samples from nine European centers were included (Germany, n = 4; Italy, n = 4; France, n = 1). Samples were drawn from 149 patients with nonsecreting adenomas (n = 32 + 2 peritumoral), subclinical hypercortisolism (n = 36), Cushing's syndrome (n = 64 + 2 peritumoral), androgen-producing tumors (n = 4), adrenocortical carcinomas (n = 5 + 2 peritumoral), and primary bilateral macronodular adrenal hyperplasias (n = 8). Blood samples were available from patients with nonsecreting adenomas (n = 15), subclinical hypercortisolism (n = 10), and Cushing's syndrome (n = 35). Clinical and hormonal data were collected. DNA amplification by PCR of exons 6 and 7 of the PRKACA gene and direct sequencing were performed. RESULTS: PRKACA heterozygous mutations were found in 22/64 samples of Cushing's syndrome patients (34%). No mutations were found in peritumoral tissue and blood samples or in other tumors examined. The c.617A>C (p.Leu206Arg) occurred in 18/22 patients. Furthermore, two novel mutations were identified: c.600_601insGTG/p.Cys200_Gly201insVal in three patients and c.639C>G+c.638_640insATTATCCTGAGG/p.Ser213Arg+p.Leu212_Lys214insIle-Ile-Leu-Arg) in one. All the mutations involved a region implicated in interaction between PKA regulatory and catalytic subunits. Patients with somatic PRKACA mutations showed higher levels of cortisol after dexamethasone test and a smaller adenoma size, compared with nonmutated subjects. CONCLUSIONS: These data confirm and extend previous observations that somatic PRKACA mutations are specific for adrenocortical adenomas causing Cushing's syndrome.
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PRKACA mutations may be associated with smaller adenomas but higher levels of cortisol production than adenomas without the mutation.
“Mutations in PRKACA may be associated with smaller adenomas but higher levels of cortisol production than adenomas where this mutation is not present (143,148).”
From Adrenal incidentaloma (2020) · cites this paper as [148]
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- Authors
- Di Dalmazi, G., Kisker, C., Calebiro, D., Mannelli, M., Canu, L., Arnaldi, G., Quinkler, M., Rayes, N., Tabarin, A., Laure Jullié, M., Mantero, F., Rubin, B., Waldmann, J., Bartsch, D. K., Pasquali, R., Lohse, M., Allolio, B., Fassnacht, M., Beuschlein, F., & Reincke, M.
- Affiliations
- University of Würzburg (DE)
- University of Florence (IT)
- Stiftung Charité (DE)
- Charité – Universitätsmedizin Berlin (DE)
- Université de Bordeaux (FR)
- University of Padua (IT)
- University of Bologna (IT)
- LMU Klinikum (DE)
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2014-10
- Volume
- 99
- Issue
- 10
- Pages
- E2093-E2100
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2048581761
- Cited by
- 119
- References
- 27
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 9 · 2023: 6 · 2022: 13 · 2021: 13 · 2020: 6 · 2019: 5 · 2018: 8 · 2017: 8 · 2016: 16 · 2015: 22 · 2014: 3
- FWCI
- 16.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Florence Research (University of Florence) (submittedVersion)
- Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- 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
- protein kinase A catalytic subunit, Cushing's syndrome, adrenal adenoma, subclinical hypercortisolism, adrenocortical carcinoma, bilateral macronodular adrenal hyperplasia
- MeSH terms
- Adrenal Cortex Neoplasms, Adult, Aged, Cushing Syndrome, Female, Heterozygote, Humans, Male, Middle Aged, Mutation, Prevalence, Adrenocortical Adenoma, White People, Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
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