Mutations in the deubiquitinase gene USP8 cause Cushing's disease

Reincke M, Sbiera S, Hayakawa A, Theodoropoulou M, Osswald A, Beuschlein F, Meitinger T, Mizuno-Yamasaki E, Kawaguchi K, Saeki Y, Tanaka K, Wieland T, Graf E, Saeger W, Ronchi CL, Allolio B, Buchfelder M, Strom TM, Fassnacht M, Komada M (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Nature Genetics Nature Publishing Group

Book Volume: 47

Pages Range: 31-8

Journal Issue: 1

DOI: 10.1038/ng.3166

Abstract

Cushing's disease is caused by corticotroph adenomas of the pituitary. To explore the molecular mechanisms of endocrine autonomy in these tumors, we performed exome sequencing of 10 corticotroph adenomas. We found somatic mutations in the USP8 deubiquitinase gene in 4 of 10 adenomas. The mutations clustered in the 14-3-3 protein binding motif and enhanced the proteolytic cleavage and catalytic activity of USP8. Cleavage of USP8 led to increased deubiqutination of the EGF receptor, impairing its downregulation and sustaining EGF signaling. USP8 mutants enhanced promoter activity of the gene encoding proopiomelanocortin. In summary, our data show that dominant mutations in USP8 cause Cushing's disease via activation of EGF receptor signaling.

Authors with CRIS profile

Michael Buchfelder Lehrstuhl für Neurochirurgie

Involved external institutions

Tokyo Institute of Technology JP Japan (JP) Julius-Maximilians-Universität Würzburg DE Germany (DE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Universität Hamburg (UHH) DE Germany (DE) University of Tokyo JP Japan (JP) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Max-Planck-Institut für Psychiatrie (Deutsche Forschungsanstalt für Psychiatrie) DE Germany (DE)

How to cite

APA:

Reincke, M., Sbiera, S., Hayakawa, A., Theodoropoulou, M., Osswald, A., Beuschlein, F.,... Komada, M. (2015). Mutations in the deubiquitinase gene USP8 cause Cushing's disease. Nature Genetics, 47(1), 31-8. https://doi.org/10.1038/ng.3166

MLA:

Reincke, Martin, et al. "Mutations in the deubiquitinase gene USP8 cause Cushing's disease." Nature Genetics 47.1 (2015): 31-8.

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