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Reincke, M.* ; Sbiera, S.* ; Hayakawa, A.* ; Theodoropoulou, M.* ; Osswald, A.* ; Beuschlein, F.* ; Meitinger, T. ; Mizuno-Yamasaki, E.* ; Kawaguchi, K.* ; Saeki, Y.* ; Tanaka, K.* ; Wieland, T. ; Graf, E. ; Saeger, W.* ; Ronchi, C.L.* ; Allolio, B.* ; Buchfelder, M.* ; Strom, T.M. ; Fassnacht, M.* ; Komada, M.*

Mutations in the deubiquitinase gene USP8 cause Cushing's disease.

Nat. Genet. 47, 31-38 (2015)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 1061-4036
e-ISSN 1546-1718
Zeitschrift Nature Genetics
Quellenangaben Band: 47, Heft: 1, Seiten: 31-38 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort New York, NY
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)