title: Mutations in the deubiquitinase gene USP8 cause Cushing's disease.
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.affiliation: Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Reincke
authors.affiliation: 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.
authors.forename: Silviu
authors.initials: S
authors.lastname: Sbiera
authors.affiliation: Department of Biological Sciences, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hayakawa
authors.affiliation: Department of Endocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Marily
authors.initials: M
authors.lastname: Theodoropoulou
authors.affiliation: Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Osswald
authors.affiliation: Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Felix
authors.identifier: 0000000178263984
authors.initials: F
authors.lastname: Beuschlein
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Department of Biological Sciences, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Mizuno-Yamasaki
authors.affiliation: Department of Biological Sciences, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Kawaguchi
authors.affiliation: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Saeki
authors.affiliation: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Graf
authors.affiliation: Institut für Neuropathologie der Universität Hamburg, Hamburg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Saeger
authors.affiliation: Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
authors.forename: Cristina L
authors.initials: CL
authors.lastname: Ronchi
authors.affiliation: 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.
authors.forename: Bruno
authors.initials: B
authors.lastname: Allolio
authors.affiliation: Neurochirurgische Klinik, Klinikum der Universität Erlangen, Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Buchfelder
authors.affiliation: 1] Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. [2] Institute of Human Genetics, Technische Universität München, Munich, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: 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.
authors.forename: Martin
authors.initials: M
authors.lastname: Fassnacht
authors.affiliation: Department of Biological Sciences, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Komada
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D049913:ACTH-Secreting Pituitary Adenoma / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D000236:Adenoma / Q000235:genetics; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D010450:Endopeptidases / Q000235:genetics* / Q000502:physiology; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics* / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism; D059472:Exome / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology; D047748:Pituitary ACTH Hypersecretion / Q000235:genetics*; D010911:Pituitary Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000502:physiology
chemical_list: D048948:14-3-3 Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D009363:Neoplasm Proteins; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D066246:ErbB Receptors; D010450:Endopeptidases; C541534:USP8 protein, human; D043222:Ubiquitin Thiolesterase