Mutations in the deubiquitinase gene USP8 cause Cushing's disease

Martin Reincke; Cristina Ronchi; Silviu Sbiera; A Hayakawa; Marily Theodoropoulou; Andrea Oswald; Felix Beuschlein; T Meitinger; E Mizuno-Yamasaki; K Kawaguchi; Y Saeki; K Tanaka; Thomas Wieland; Elisabeth Graaf; Wolfgang Saeger; Bruno Allolio; Michael Buchfelder; Tim M Strom; Martin Fassnacht; Masa Komada

doi:10.1038/ng.3166

Mutations in the deubiquitinase gene USP8 cause Cushing's disease

Martin Reincke, Cristina Ronchi, Silviu Sbiera, A Hayakawa, Marily Theodoropoulou, Andrea Oswald, Felix Beuschlein, T Meitinger, E Mizuno-Yamasaki , K Kawaguchi, Y Saeki, K Tanaka, Thomas Wieland, Elisabeth Graaf, Wolfgang Saeger, Bruno Allolio, Michael Buchfelder, Tim M Strom, Martin Fassnacht, Masa Komada

Metabolism and Systems Research

Research output: Contribution to journal › Article › peer-review

268 Citations (Scopus)

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.

Original language	English
Pages (from-to)	31-38
Number of pages	8
Journal	Nature Genetics
Volume	47
Issue number	1
Early online date	8 Dec 2014
DOIs	https://doi.org/10.1038/ng.3166
Publication status	Published - Jan 2015

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Reincke, M., Ronchi, C., Sbiera, S., Hayakawa, A., Theodoropoulou, M., Oswald, A., Beuschlein, F., Meitinger, T., Mizuno-Yamasaki , E., Kawaguchi, K., Saeki, Y., Tanaka, K., Wieland, T., Graaf, E., Saeger, W., Allolio, B., Buchfelder, M., Strom, T. M., Fassnacht, M., & Komada, M. (2015). Mutations in the deubiquitinase gene USP8 cause Cushing's disease. Nature Genetics, 47(1), 31-38. Advance online publication. https://doi.org/10.1038/ng.3166

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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.",

author = "Martin Reincke and Cristina Ronchi and Silviu Sbiera and A Hayakawa and Marily Theodoropoulou and Andrea Oswald and Felix Beuschlein and T Meitinger and E Mizuno-Yamasaki and K Kawaguchi and Y Saeki and K Tanaka and Thomas Wieland and Elisabeth Graaf and Wolfgang Saeger and Bruno Allolio and Michael Buchfelder and Strom, {Tim M} and Martin Fassnacht and Masa Komada",

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Reincke, M, Ronchi, C, Sbiera, S, Hayakawa, A, Theodoropoulou, M, Oswald, A, Beuschlein, F, Meitinger, T, Mizuno-Yamasaki , E, Kawaguchi, K, Saeki, Y, Tanaka, K, Wieland, T, Graaf, E, Saeger, W, Allolio, B, Buchfelder, M, Strom, TM, Fassnacht, M & Komada, M 2015, 'Mutations in the deubiquitinase gene USP8 cause Cushing's disease', Nature Genetics, vol. 47, no. 1, pp. 31-38. https://doi.org/10.1038/ng.3166

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T1 - Mutations in the deubiquitinase gene USP8 cause Cushing's disease

AU - Reincke, Martin

AU - Ronchi, Cristina

AU - Sbiera, Silviu

AU - Hayakawa, A

AU - Theodoropoulou, Marily

AU - Oswald, Andrea

AU - Beuschlein, Felix

AU - Meitinger, T

AU - Mizuno-Yamasaki , E

AU - Kawaguchi, K

AU - Saeki, Y

AU - Tanaka, K

AU - Wieland, Thomas

AU - Graaf, Elisabeth

AU - Saeger, Wolfgang

AU - Allolio, Bruno

AU - Buchfelder, Michael

AU - Strom, Tim M

AU - Fassnacht, Martin

AU - Komada, Masa

PY - 2015/1

Y1 - 2015/1

N2 - 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.

AB - 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.

U2 - 10.1038/ng.3166

DO - 10.1038/ng.3166

M3 - Article

SN - 1061-4036

VL - 47

SP - 31

EP - 38

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

Mutations in the deubiquitinase gene USP8 cause Cushing's disease

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