ArticleThe Journal of clinical endocrinology and metabolism2018
Glucocorticoid Receptor Mutations and Hypersensitivity to Endogenous and Exogenous Glucocorticoids.
Article in The Journal of clinical endocrinology and metabolism, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
16 citing papers in PubMed, 24 citations in OpenAlex.
- Is evaluation of cortisol after dexamethasone suppression test enough? Analysis of steroid profile after dexamethasone suppression test using tandem mass spectrometry.Endocrine connections · 2025Article
- Chronic Stress and Headaches: The Role of the HPA Axis and Autonomic Nervous System.Biomedicines · 2025Review
- Neuroprotective effects of total phenolics fromFrontiers in pharmacology · 2024Article
- Recognition of Nonneoplastic Hypercortisolism in the Evaluation of Patients With Cushing Syndrome.Journal of the Endocrine Society · 2023Article
- Approach to the Patient: Diagnosis of Cushing Syndrome.The Journal of clinical endocrinology and metabolism · 2022Article
- Two cases of infantile-onset primary generalized glucocorticoid hypersensitivity and the effect of mifepristone.BMC pediatrics · 2022Article
- Sleep fragmentation engages stress-responsive circuitry, enhances inflammation and compromises hippocampal function following traumatic brain injury.Experimental neurology · 2022Article
- Cardiometabolic Health in Adolescents and Young Adults with Congenital Adrenal Hyperplasia.Medicina (Kaunas, Lithuania) · 2022Article
- Variation in glucocorticoid sensitivity and the relation with obesity.Obesity reviews : an official journal of the International Association for the Study of Obesity · 2022Review
- Glucocorticoid Resistance: Interference between the Glucocorticoid Receptor and the MAPK Signalling Pathways.International journal of molecular sciences · 2021Review
- Differential Effects of Fkbp4 and Fkbp5 on Regulation of theInternational journal of molecular sciences · 2021Article
- Investigation of the effect of Huaiqihuang granules via adjuvant treatment in children with relapsed systemic lupus erythematosus.American journal of translational research · 2021Article
- Moderate Aerobic Exercise Training Prevents the Augmented Hepatic Glucocorticoid Response Induced by High-Fat Diet in Mice.International journal of molecular sciences · 2020Article
- Glucocorticoid receptor mutations and clinical sensitivity to glucocorticoid in Chinese multiple sclerosis patients.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2020Article
- A Novel Pathogenic Variant in the N-Terminal Domain of the Glucocorticoid Receptor, Causing Glucocorticoid Resistance.Molecular diagnosis & therapy · 2020Article
- Functional Characterization of Glucocorticoid Receptor Variants Is Required to Avoid Misinterpretation of NGS Data.Journal of the Endocrine Society · 2019Article
Corrections and comments
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Authors and funding
7 authors at 5 institutions in 1 country.
Funding
Abstract
Background: The glucocorticoid receptor (GR) consists of two alternatively spliced isoforms: GRα, which activates gene transcription, and GRβ, a dominant-negative receptor. Theoretically, inactivating variants of GRβ could result in glucocorticoid hypersensitivity. Design: A 46-year-old woman presented for evaluation of adrenal insufficiency prompted by low plasma cortisol levels and multiple unexplained symptoms but without clinical evidence of glucocorticoid insufficiency. To explain these findings, extensive clinical, genetic, and molecular studies were performed. Methods: Standard clinical methods assessed the patient's hypothalamic-pituitary-adrenal axis. Validated molecular techniques were used for receptor sequencing, stable transfections, stimulation of candidate genes, cDNA arrays, Ingenuity Pathway Analysis, volcano analysis, and isolation and analysis of the patient's mononuclear cells. Results: Clinical studies excluded primary or secondary adrenal insufficiency, established consistently low basal cortisol levels, and demonstrated hypersensitivity to ultra-low-dose dexamethasone. Receptor sequencing identified two variants of GR9β (A3669G and G3134T) as well as the known Bcl1 polymorphism. Reductionist studies using stable osteosarcoma cell lines transfected with the GRβ variants demonstrated glucocorticoid hypersensitivity of transcribed genes on cDNA array analysis. The patient's monocytes responded to hydrocortisone with exaggerated stimulation of the candidate genes GILZ and FKBP5. Conclusion: Two variants of the dominant-negative GRβ, in conjunction with a common Bcl1 intron variant, resulted in hypersensitivity to endogenous and exogenous glucocorticoids and, as a reflection of severity, low circulating cortisol levels without clinical evidence of glucocorticoid insufficiency. This prismatic case exemplifies the unique effects of variants of a dominant-negative receptor.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.