Mutations in the deubiquitinase gene USP8 cause Cushing's disease

Nat Genet. 2015 Jan;47(1):31-8. doi: 10.1038/ng.3166.

Martin Reincke ¹, Silviu Sbiera ², Akira Hayakawa ³, Marily Theodoropoulou ⁴, Andrea Osswald ¹, Felix Beuschlein ¹, Thomas Meitinger ⁵, Emi Mizuno-Yamasaki ³, Kohei Kawaguchi ³, Yasushi Saeki ⁶, Keiji Tanaka ⁶, Thomas Wieland ⁷, Elisabeth Graf ⁷, Wolfgang Saeger ⁸, Cristina L Ronchi ⁹, Bruno Allolio ¹⁰, Michael Buchfelder ¹¹, Tim M Strom ¹², Martin Fassnacht ¹³, Masayuki Komada ³

Affiliations

1 Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany.
2 1] Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany. [2] Department of Medicine I, Endocrine and Diabetes Unit, University Hospital, University of Würzburg, Würzburg, Germany.
3 Department of Biological Sciences, Tokyo Institute of Technology, Yokohama, Japan.
4 Department of Endocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
5 1] Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. [2] Institute of Human Genetics, Technische Universität München, Munich, Germany. [3] DZHK (German Centre for Cardiovascular Research) partner site, Munich Heart Alliance, Munich, Germany.
6 Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
7 Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
8 Institut für Neuropathologie der Universität Hamburg, Hamburg, Germany.
9 Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
10 1] Department of Medicine I, Endocrine and Diabetes Unit, University Hospital, University of Würzburg, Würzburg, Germany. [2] Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany.
11 Neurochirurgische Klinik, Klinikum der Universität Erlangen, Erlangen, Germany.
12 1] Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. [2] Institute of Human Genetics, Technische Universität München, Munich, Germany.
13 1] Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany. [2] Department of Medicine I, Endocrine and Diabetes Unit, University Hospital, University of Würzburg, Würzburg, Germany. [3] Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.

PMID: 25485838 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.

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