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  3. A novel nonsense mutation of the glucocorticoid receptor gene causing glucocorticoid resistance with infertility

A novel nonsense mutation of the glucocorticoid receptor gene causing glucocorticoid resistance with infertility

  • Endocrine. 2025 May 24. doi: 10.1007/s12020-025-04280-1.
Jiangyun Lei # 1,  Yue Wang # 1,  Ying Song 1,  Chuan Peng 1,  Zhipeng Wu 1,  Yunjie Xiong 1,  Furong He 1,  Ting Luo 1,  Yu Fang 2,  Yong Xu 3,  Wei Huang 3,  Jinbo Hu 1,  Shumin Yang 4,  Qifu Li 5,  Linqiang Ma 6
Affiliations

Affiliations

  • 1 Department of Endocrinology, Sichuan-Chongqing Joint Key Laboratory of Metabolic Vascular Diseases, Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2 Department of Endocrinology, the Tongnan District People's Hospital, Chongqing, China.
  • 3 Department of Endocrinology and Metabolism, Sichuan-Chongqing Joint Key Laboratory of Metabolic Vascular Diseases, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
  • 4 Department of Endocrinology, Sichuan-Chongqing Joint Key Laboratory of Metabolic Vascular Diseases, Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China. 443068494@qq.com.
  • 5 Department of Endocrinology, Sichuan-Chongqing Joint Key Laboratory of Metabolic Vascular Diseases, Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China. liqifu@yeah.net.
  • 6 Department of Endocrinology, Sichuan-Chongqing Joint Key Laboratory of Metabolic Vascular Diseases, Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China. tom_linqiang@163.com.
  • # Contributed equally.
PMID: 40413280 DOI: 10.1007/s12020-025-04280-1
Abstract

Purpose: Chrousos syndrome is a rare disease mainly caused by inactivated mutations in the NR3C1 gene, which encodes the human Glucocorticoid Receptor (GR). We reported a male patient of Chrousos syndrome, who had a novel nonsense mutation (c.1839T > A, p. Tyr613Ter) in NR3C1 and presented with oligospermic and infertility but without Other typical clinical manifestation. The aim of this study is to explore the molecular mechanisms that cause the unique clinical manifestations in this patient.

Methods: Mutant plasmids were transfected to HEK293T and HeLa cells to evaluate glucocorticoid sensitivity and GR expression. Proteomic and further cellular experiments were used to illustrate the mechanism of GR expression change induced by mutation.

Results: The mutation causes the deletion of the ligand-binding region of the GR (GR Y613*). Compared with GR wild type (GR WT), GR Y613* had a decreased affinity with dexamethasone, reduced nuclear translocation and decreased transactivation of the glucocorticoid response gene mouse mammary tumor virus promoter. GR Y613* caused decreased protein but unchanged gene expression. E3 Ligase STUB1 was identified to regulate ubiquitin-proteasome degradation of GR Y613*. Compared with Other human tissues and cell types, expression of STUB1 in testis and Sertoli cells was low.

Conclusions: GR Y613* causes reduced sensitivity to glucocorticoids. STUB1 promotes ubiquitination and degradation of GR Y613*. Low expression of STUB1 in human testis compared with Other tissue might cause accumulation of GR Y613*, as a potential explanation of the infertility of Chrousos syndrome.

Keywords

NR3C1 gene; Chrousos syndrome; Glucocorticoid receptor; Infertility.

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