Characterization of a Novel Variant in the NR3C1 Gene

Margaux Laulhé, Michal Yacobi Bach, Julie Perrot, Michal Gershinsky, Jérôme Fagart, Gabi Shefer, Larbi Amazit, Peter Kamenický, Say Viengchareun, Laetitia Martinerie, Yona Greenman
The Journal of Clinical Endocrinology & Metabolism, Volume 110, Issue 8, August 2025, Pages e2621–e2630
https://doi.org/10.1210/clinem/dgae829

Abstract

Context

Primary generalized glucocorticoid resistance syndrome (GGRS) is a rare endocrine disease caused by loss-of-function variants of the NR3C1 gene encoding the glucocorticoid receptor (GR).

Objective

We describe a novel heterozygous missense variant (NM_000176.3, c.1330T>G, p.Phe444Val) within the DNA-binding domain.

Clinical Case

Elevated urinary free cortisol levels were detected in a 59-year-old male patient before bariatric surgery (body mass index 39.9 kg/m²). Early-onset hypertension was well controlled. The low-dose dexamethasone suppression test was pathologic, but ACTH and midnight salivary cortisol levels were normal. The patient was initially referred to transsphenoidal surgery for a presumed diagnosis of Cushing disease. He presented to our department at the age of 68, when the clinical diagnosis of GGRS was established.

Methods

Functional characterization of the variant was performed ex vivo through transient transfection assays in HEK 293T cells to assess transcriptional activity and nuclear translocation.

Results

The variant showed a lack of transcriptional activity (GR_WT: 91.5 [80.5; 101.2] vs GR_F444V: 1.0 [1.0; 1.0]) despite efficient nuclear translocation in response to dexamethasone, suggesting a DNA binding defect of the variant. These results are discussed in the light of previously reported GGRS cases.

Conclusion

We have described a novel heterozygous mutation of the NR3C1 gene associated with primary GGRS. This case highlights the importance of raising awareness of clinical and laboratory features of this rare disorder, to enable early diagnosis and avoid unnecessary and potentially dangerous diagnostic and therapeutic procedures.

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