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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Acknowledgements

We thank Minoru Fukuda and Mitsunori Fukuda for the LAMP2 antibody and EGFP-Rab11AS25A expression vector, respectively. The study was supported in by the Else Kröner-Fresenius-Stiftung (grant 2012_A103 to M.R.), Bundesministerium für Bildung und Forschung (grant BMBF 01EO1004-D2 to M.F. and B.A.), the Wilhelm Sander-Stiftung (grant 2012.095.1 to B.A.), and Grants-in-aid from the Ministry of Education, Culture, Science and Technology of Japan (grant 24112003 to M.K. and 24112008 to Y.S.). W.S. is supported by funds from Novartis AG, Pfizer and NovoNordisk and Ipsen for the Hypophysenregister der Arbeitsgemeinschaft Hypophyse of the German Society of Endocrinology. M.T. is supported by a grant from the German Federal Ministry of Education and Research (01EX1021B, Spitzencluster M4, Verbund Personalisierte Medizin, Teilprojekt NeoExNET (PM1)). We thank B. Mauracher, P. Rank, J. Stalla and J.L. Monteserin-Garcia for excellent technical assistance.

Author information

Author notes

    • Martin Reincke
    • , Silviu Sbiera
    • , Akira Hayakawa
    • , Marily Theodoropoulou
    • , Michael Buchfelder
    • , Tim M Strom
    • , Martin Fassnacht
    •  & Masayuki Komada

    These authors contributed equally to this work.

Affiliations

  1. Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany.

    • Martin Reincke
    • , Silviu Sbiera
    • , Andrea Osswald
    • , Felix Beuschlein
    •  & Martin Fassnacht
  2. Department of Medicine I, Endocrine and Diabetes Unit, University Hospital, University of Würzburg, Würzburg, Germany.

    • Silviu Sbiera
    • , Bruno Allolio
    •  & Martin Fassnacht
  3. Department of Biological Sciences, Tokyo Institute of Technology, Yokohama, Japan.

    • Akira Hayakawa
    • , Emi Mizuno-Yamasaki
    • , Kohei Kawaguchi
    •  & Masayuki Komada
  4. Department of Endocrinology, Max Planck Institute of Psychiatry, Munich, Germany.

    • Marily Theodoropoulou
  5. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.

    • Thomas Meitinger
    • , Thomas Wieland
    • , Elisabeth Graf
    •  & Tim M Strom
  6. Institute of Human Genetics, Technische Universität München, Munich, Germany.

    • Thomas Meitinger
    •  & Tim M Strom
  7. DZHK (German Centre for Cardiovascular Research) partner site, Munich Heart Alliance, Munich, Germany.

    • Thomas Meitinger
  8. Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

    • Yasushi Saeki
    •  & Keiji Tanaka
  9. Institut für Neuropathologie der Universität Hamburg, Hamburg, Germany.

    • Wolfgang Saeger
  10. Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.

    • Cristina L Ronchi
    •  & Martin Fassnacht
  11. Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany.

    • Bruno Allolio
  12. Neurochirurgische Klinik, Klinikum der Universität Erlangen, Erlangen, Germany.

    • Michael Buchfelder

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Contributions

M.R., M.F. and M.K. planned the study, conceived and designed the experiments, analyzed the data and wrote the paper. S.S., A.H., M.T., F.B., T.M., E.M.-Y., K.K., T.W., E.G. W.S., B.A. and T.M.S. designed and performed experiments and analyzed data. A.O., Y. S., K.T. and C.L.R. performed experiments. M.B. provided tumor tissue and clinical data.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Martin Reincke or Martin Fassnacht.

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DOI

https://doi.org/10.1038/ng.3166

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