Effect of 3 NR3C1 Mutations in the Pathogenesis of Pituitary ACTH Adenoma
© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissionsoup.com..
CONTEXT: Glucocorticoids act through the glucocorticoid receptor (GR) encoded by the nuclear receptor subfamily 3 group C member 1 (NR3C1) gene.
OBJECTIVE: This study aimed to examine the function of NR3C1 variants and their possible pathogenic role in Cushing disease (CD).
METHODS: Next-generation sequencing was conducted in 49 CD patients. Corticotroph tumor GR protein expression was examined by immunohistochemistry (IHC). Constructs harboring the 3 NR3C1-mutant and wild-type (WT) GR were transfected into the murine corticotropic adenoma cell line (AtT-20), and GR protein expression was quantified by Western blot. Translocation activity was assessed by immunofluorescence and effects of the GR mutants on corticotroph tumor proliferation, pro-opiomelanocortin (POMC) transcription, and ACTH secretion were tested.
RESULTS: Clinical features were similar in patients harboring the NR3C1 mutations and WT GR. Recurrent adenomas showed higher GR IHC scores than nonrecurrent tumors. In vitro studies demonstrated that the p.R469X mutant generated a truncated GR protein, and the p.D590G and p.Y693D GR mutants resulted in lower GR expression. Dexamethasone (DEX) treatment of AtT-20 cells demonstrated decreased DEX-induced nuclear translocation, increased cell proliferation, and attenuated suppression of POMC transcription of 3 GR mutants. Interestingly, the p.R469X GR mutant resulted in increased murine corticotroph tumor ACTH secretion compared to WT GR.
CONCLUSION: Our findings identify 3/49 (6.1%) consecutive human corticotroph tumors harboring GR mutations. Further findings demonstrate the role NR3C1 plays in CD pathogenesis and offer insights into a novel treatment approach in this patient subset.
| Errataetall: |
CommentIn: Endocrinology. 2022 Feb 1;163(2):. - PMID 34935938 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:162 |
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| Enthalten in: |
Endocrinology - 162(2021), 11 vom: 01. Nov. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Miao, Hui [VerfasserIn] |
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| Links: |
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| Themen: |
Cushing disease |
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| Anmerkungen: |
Date Completed 11.01.2022 Date Revised 11.01.2022 published: Print CommentIn: Endocrinology. 2022 Feb 1;163(2):. - PMID 34935938 Citation Status MEDLINE |
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| doi: |
10.1210/endocr/bqab167 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM329708880 |
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| 100 | 1 | |a Miao, Hui |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Effect of 3 NR3C1 Mutations in the Pathogenesis of Pituitary ACTH Adenoma |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 11.01.2022 | ||
| 500 | |a Date Revised 11.01.2022 | ||
| 500 | |a published: Print | ||
| 500 | |a CommentIn: Endocrinology. 2022 Feb 1;163(2):. - PMID 34935938 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissionsoup.com. | ||
| 520 | |a CONTEXT: Glucocorticoids act through the glucocorticoid receptor (GR) encoded by the nuclear receptor subfamily 3 group C member 1 (NR3C1) gene | ||
| 520 | |a OBJECTIVE: This study aimed to examine the function of NR3C1 variants and their possible pathogenic role in Cushing disease (CD) | ||
| 520 | |a METHODS: Next-generation sequencing was conducted in 49 CD patients. Corticotroph tumor GR protein expression was examined by immunohistochemistry (IHC). Constructs harboring the 3 NR3C1-mutant and wild-type (WT) GR were transfected into the murine corticotropic adenoma cell line (AtT-20), and GR protein expression was quantified by Western blot. Translocation activity was assessed by immunofluorescence and effects of the GR mutants on corticotroph tumor proliferation, pro-opiomelanocortin (POMC) transcription, and ACTH secretion were tested | ||
| 520 | |a RESULTS: Clinical features were similar in patients harboring the NR3C1 mutations and WT GR. Recurrent adenomas showed higher GR IHC scores than nonrecurrent tumors. In vitro studies demonstrated that the p.R469X mutant generated a truncated GR protein, and the p.D590G and p.Y693D GR mutants resulted in lower GR expression. Dexamethasone (DEX) treatment of AtT-20 cells demonstrated decreased DEX-induced nuclear translocation, increased cell proliferation, and attenuated suppression of POMC transcription of 3 GR mutants. Interestingly, the p.R469X GR mutant resulted in increased murine corticotroph tumor ACTH secretion compared to WT GR | ||
| 520 | |a CONCLUSION: Our findings identify 3/49 (6.1%) consecutive human corticotroph tumors harboring GR mutations. Further findings demonstrate the role NR3C1 plays in CD pathogenesis and offer insights into a novel treatment approach in this patient subset | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a NR3C1 | |
| 650 | 4 | |a Cushing disease | |
| 650 | 4 | |a glucocorticoid receptor | |
| 650 | 4 | |a pituitary ACTH-secreting adenoma | |
| 650 | 7 | |a NR3C1 protein, human |2 NLM | |
| 650 | 7 | |a Receptors, Glucocorticoid |2 NLM | |
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| 700 | 1 | |a Lu, Lin |e verfasserin |4 aut | |
| 700 | 1 | |a Gong, Fengying |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Linjie |e verfasserin |4 aut | |
| 700 | 1 | |a Duan, Lian |e verfasserin |4 aut | |
| 700 | 1 | |a Yao, Yong |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Renzhi |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Shi |e verfasserin |4 aut | |
| 700 | 1 | |a Mao, Xinxin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Dongyun |e verfasserin |4 aut | |
| 700 | 1 | |a Heaney, Anthony P |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Huijuan |e verfasserin |4 aut | |
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