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: Martin Reincke, Silviu Sbiera, Akira Hayakawa, Marily Theodoropoulou, Andrea Osswald, Felix Beuschlein, Thomas Meitinger, Emi Mizuno-Yamasaki, Kohei Kawaguchi, Yasushi Saeki, Keiji Tanaka, Thomas Wieland, Elisabeth Graf, Wolfgang Saeger, Cristina L Ronchi, Bruno Allolio, Michael Buchfelder, Tim M Strom, Martin Fassnacht, Masayuki Komada
• Journal: Nature genetics (Nat Genet) Vol. 47 Issue 1 Pg. 31-8 (Jan 2015) ISSN: 1546-1718 [Electronic] United States
• PMID: 25485838 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 14-3-3 Proteins
• Endosomal Sorting Complexes Required for Transport
• Neoplasm Proteins
• Pro-Opiomelanocortin
• Adrenocorticotropic Hormone
• ErbB Receptors
• Endopeptidases
• USP8 protein, human
• Ubiquitin Thiolesterase

Topics

• 14-3-3 Proteins (metabolism)
• ACTH-Secreting Pituitary Adenoma (complications, genetics, metabolism)
• Adenoma (genetics)
• Adrenocorticotropic Hormone (metabolism)
• Amino Acid Sequence
• Animals
• COS Cells
• Chlorocebus aethiops
• Endopeptidases (genetics, physiology)
• Endosomal Sorting Complexes Required for Transport (genetics, physiology)
• ErbB Receptors (metabolism)
• Exome (genetics)
• Gene Expression Regulation, Neoplastic
• Humans
• Molecular Sequence Data
• Mutation
• Neoplasm Proteins (genetics, physiology)
• Pituitary ACTH Hypersecretion (genetics)
• Pituitary Neoplasms (complications, genetics, metabolism)
• Pro-Opiomelanocortin (biosynthesis, genetics)
• Sequence Alignment
• Sequence Homology, Amino Acid
• Ubiquitin Thiolesterase (genetics, physiology)