The Gene of the Ubiquitin-Specific Protease 8 Is Frequently Mutated in Adenomas Causing Cushing's Disease

Perez-Rivas LG, Theodoropoulou M, Ferrau F, Nusser C, Kawaguchi K, Stratakis CA, Faucz FR, Wildemberg LE, Assie G, Beschorner R, Dimopoulou C, Buchfelder M, Popovic V, Berr CM, Toth M, Ardisasmita AI, Honegger J, Bertherat J, Gadelha MR, Beuschlein F, Stalla G, Komada M, Korbonits M, Reincke M (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Journal of Clinical Endocrinology and Metabolism Oxford University Press

Book Volume: 100

Pages Range: E997-1004

Journal Issue: 7

DOI: 10.1210/jc.2015-1453

Abstract

We have recently reported somatic mutations in the ubiquitin-specific protease USP8 gene in a small series of adenomas of patients with Cushing's disease.To determine the prevalence of USP8 mutations and the genotype-phenotype correlation in a large series of patients diagnosed with Cushing's disease.We performed a retrospective, multicentric, genetic analysis of 134 functioning and 11 silent corticotroph adenomas using Sanger sequencing. Biochemical and clinical features were collected and examined within the context of the mutational status of USP8, and new mutations were characterized by functional studies.A total of 145 patients who underwent surgery for an ACTH-producing pituitary adenoma.Mutational status of USP8. Biochemical and clinical features included sex, age at diagnosis, tumor size, preoperative and postoperative hormonal levels, and comorbidities.We found somatic mutations in USP8 in 48 (36%) pituitary adenomas from patients with Cushing's disease but in none of 11 silent corticotropinomas. The prevalence was higher in adults than in pediatric cases (41 vs 17%) and in females than in males (43 vs 17%). Adults having USP8-mutated adenomas were diagnosed at an earlier age than those with wild-type lesions (36 vs 44 y). Mutations were primarily found in adenomas of 10 ± 7 mm and were inversely associated with the development of postoperative adrenal insufficiency. All the mutations affected the residues Ser718 or Pro720, including five new identified alterations. Mutations reduced the interaction between USP8 and 14-3-3 and enhanced USP8 activity. USP8 mutants diminished epidermal growth factor receptor ubiquitination and induced Pomc promoter activity in immortalized AtT-20 corticotropinoma cells.USP8 is frequently mutated in adenomas causing Cushing's disease, especially in those from female adult patients diagnosed at a younger age.

Authors with CRIS profile

Michael Buchfelder Lehrstuhl für Neurochirurgie

Involved external institutions

Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Queen Mary, University of London GB United Kingdom (GB) Tokyo Institute of Technology JP Japan (JP) Max-Planck-Institut für Psychiatrie (Deutsche Forschungsanstalt für Psychiatrie) DE Germany (DE) Universidade Federal do Rio de Janeiro (UFRJ) / Federal University of Rio de Janeiro BR Brazil (BR) University of Paris 5 - René Descartes / Université Paris V René Descartes FR France (FR) Eberhard Karls Universität Tübingen DE Germany (DE) Semmelweis University / Semmelweis Egyetem HU Hungary (HU) University of Belgrade / Универзитет у Београду RS Serbia (RS) Eunice Kennedy Shriver National Institute of Child Health and Human Development US United States (USA) (US)

How to cite

APA:

Perez-Rivas, L.G., Theodoropoulou, M., Ferrau, F., Nusser, C., Kawaguchi, K., Stratakis, C.A.,... Reincke, M. (2015). The Gene of the Ubiquitin-Specific Protease 8 Is Frequently Mutated in Adenomas Causing Cushing's Disease. Journal of Clinical Endocrinology and Metabolism, 100(7), E997-1004. https://dx.doi.org/10.1210/jc.2015-1453

MLA:

Perez-Rivas, Luis G., et al. "The Gene of the Ubiquitin-Specific Protease 8 Is Frequently Mutated in Adenomas Causing Cushing's Disease." Journal of Clinical Endocrinology and Metabolism 100.7 (2015): E997-1004.

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