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Genetics of Cushing’s disease: an update

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Abstract

Introduction

Cushing’s disease (CD) results from uncontrolled hypercortisolism induced by ACTH-secreting corticotroph adenomas; accordingly, patients diagnosed with CD usually present several comorbidities and an increased risk of mortality. Hypothesis-driven screenings have led to identification of rare alterations in a low number of patients, although the genetic basis underlying CD has remained unclear until recently. Using whole-exome sequencing, recurrent mutations have been reported in the gene coding for the ubiquitin-specific protease 8 (USP8), a protein with deubiquitinase (DUB) activity that modulates the lysosomal turnover of the EGF receptor (EGFR) and other membrane proteins.

Methods

In this review, we summarize the recent genetic findings and discuss the clinical and pathological implications of USP8 deregulation in corticotroph adenomas.

Conclusions

Mutations in USP8 have been identified in 35–62 % of functional sporadic corticotroph adenomas causing Cushing’s disease, but not in any other type of pituitary tumor. These mutations are found mostly in adult female patients and lead to an aberrant DUB activation by impairing the regulation of USP8 by members of the 14-3-3 family of proteins. The consequence of this hyperactivation is a longer retention of EGFR at the plasma membrane which promotes an enhanced production of ACTH.

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Abbreviations

CD:

Cushing’s disease

ACTH:

Adrenocorticotropic hormone

POMC:

Pro-opiomelacortin

USP8:

Ubiquitin-specific protease 8

DUB:

Deubiquitinase

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

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Acknowledgments

M.R. is supported by the Else Kröner-Fresenius-Stiftung (Grant # 2012_A103) and the German Research Foundation (DFG, Grant # RE 752/20-1). L.G.P.R. is supported by funds from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007–2013) under REA Grant Agreement No. 608765.

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Authors and Affiliations

  1. Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Ziemssenstrasse 1, 80336, Munich, Germany

    L. G. Perez-Rivas & M. Reincke

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  1. L. G. Perez-Rivas
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  2. M. Reincke
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Correspondence to M. Reincke.

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Perez-Rivas, L.G., Reincke, M. Genetics of Cushing’s disease: an update. J Endocrinol Invest 39, 29–35 (2016). https://doi.org/10.1007/s40618-015-0353-0

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