1. Academic Validation
  2. Effect of 3 NR3C1 Mutations in the Pathogenesis of Pituitary ACTH Adenoma

Effect of 3 NR3C1 Mutations in the Pathogenesis of Pituitary ACTH Adenoma

  • Endocrinology. 2021 Nov 1;162(11):bqab167. doi: 10.1210/endocr/bqab167.
Hui Miao 1 Yang Liu 1 Lin Lu 1 Fengying Gong 1 Linjie Wang 1 Lian Duan 1 Yong Yao 2 Renzhi Wang 2 Shi Chen 1 Xinxin Mao 3 Dongyun Zhang 4 Anthony P Heaney 4 Huijuan Zhu 1
Affiliations

Affiliations

  • 1 Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, P. R. China.
  • 2 Department of Neurosurgery, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, P. R. China.
  • 3 Department of Pathology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing 100730, P. R. China.
  • 4 Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
Abstract

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.

Keywords

NR3C1; Cushing disease; glucocorticoid receptor; pituitary ACTH-secreting adenoma.

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