title: Genetics of Cushing's disease: an update.
abstract: BACKGROUND
  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.
authors.affiliation: Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Ziemssenstrasse 1, 80336, Munich, Germany. luis.perez@med.lmu.de.
authors.forename: L G
authors.identifier: http://orcid.org/0000-0002-2555-0602
authors.initials: LG
authors.lastname: Perez-Rivas
authors.affiliation: Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Ziemssenstrasse 1, 80336, Munich, Germany. martin.reincke@med.uni-muenchen.de.
authors.forename: M
authors.initials: M
authors.lastname: Reincke
mesh_terms: D049913:ACTH-Secreting Pituitary Adenoma / Q000453:epidemiology / Q000235:genetics; D000236:Adenoma / Q000453:epidemiology / Q000235:genetics; D000328:Adult; D000595:Amino Acid Sequence; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D047748:Pituitary ACTH Hypersecretion / Q000453:epidemiology / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; C512478:EGFR protein, human; D066246:ErbB Receptors; D010450:Endopeptidases; C541534:USP8 protein, human; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases
keywords: ACTH; Cushing’s disease; EGFR; Pituitary tumor; USP8