Mutations in the deubiquitinase gene USP8 cause Cushing's disease

• Published in: Nature genetics Vol. 47; no. 1; pp. 31 - 38
• Main Authors: Reincke, Martin, Sbiera, Silviu, Hayakawa, Akira, Theodoropoulou, Marily, Osswald, Andrea, Beuschlein, Felix, Meitinger, Thomas, Mizuno-Yamasaki, Emi, Kawaguchi, Kohei, Saeki, Yasushi, Tanaka, Keiji, Wieland, Thomas, Graf, Elisabeth, Saeger, Wolfgang, Ronchi, Cristina L, Allolio, Bruno, Buchfelder, Michael, Strom, Tim M, Fassnacht, Martin, Komada, Masayuki
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2015; Nature Publishing Group
• Subjects: 13/109; 14-3-3 Proteins - metabolism; 14/63; 45; 45/47; 692/699/2743/2742/1738; 82/51; 82/58; 82/81; ACTH-Secreting Pituitary Adenoma - complications; ACTH-Secreting Pituitary Adenoma - genetics; ACTH-Secreting Pituitary Adenoma - metabolism; ACTH-Secreting Pituitary Adenoma - secretion; Adenoma - genetics; Adrenocorticotropic Hormone - secretion; Agriculture; Amino Acid Sequence; Animal Genetics and Genomics; Animals; Biomedicine; Cancer Research; Cercopithecus aethiops; COS Cells; Cushing syndrome; Endopeptidases - genetics; Endopeptidases - physiology; Endosomal Sorting Complexes Required for Transport - genetics; Endosomal Sorting Complexes Required for Transport - physiology; Exome - genetics; Gene Expression Regulation, Neoplastic; Gene Function; Gene mutations; Genes; Genetic aspects; Health aspects; Human Genetics; Humans; Kinases; Molecular Sequence Data; Mutation; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Physiological aspects; Pituitary ACTH Hypersecretion - genetics; Pituitary gland; Pituitary Neoplasms - complications; Pituitary Neoplasms - genetics; Pituitary Neoplasms - metabolism; Pituitary Neoplasms - secretion; Pro-Opiomelanocortin - biosynthesis; Pro-Opiomelanocortin - genetics; Receptor, Epidermal Growth Factor - metabolism; Risk factors; Rodents; Sequence Alignment; Sequence Homology, Amino Acid; Tumors; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - physiology; Ubiquitin-proteasome system; Germany
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.3166

Martin Reincke, Martin Fassnacht and colleagues identify somatic mutations in the USP8 deubiquitinase gene in corticotroph adenomas in Cushing's disease. The mutations enhanced proteolytic cleavage and catalytic activity of USP8, which led to activation of EGF receptor signaling. 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.