A novel mutation in the NR3C1 gene associated with reversible glucocorticoid resistance

被引:1
作者
Laulhe, Margaux [1 ]
Kuhn, Emmanuelle [2 ]
Bouligand, Jerome [1 ,3 ]
Amazit, Larbi [4 ]
Perrot, Julie [1 ]
Lebigot, Elise [5 ]
Kamenicky, Peter [1 ,6 ]
Lombes, Marc [1 ]
Fagart, Jerome [7 ]
Viengchareun, Say [1 ,11 ]
Martinerie, Laetitia [1 ,8 ,9 ,10 ]
机构
[1] Univ Paris Saclay, Inserm, Physiol & Physiopathol Endocriniennes, F-94276 Le Kremlin Bicetre, France
[2] Hop La Pitie Salpetriere, AP HP, Unite Hypophyse, F-75013 Paris, France
[3] Univ Paris Saclay, Hop Bicetre, APHP Paris Saclay, Serv Genet Mol Pharmacogenet & Hormonol, F-94270 Le Kremlin Bicetre, France
[4] Univ Paris Saclay, Inst Biomed Val de Bievre, UMS 44, F-94276 Le Kremlin Bicetre, France
[5] Hop Bicetre, APHP Paris Saclay, Serv Biochim, F-94270 Le Kremlin Bicetre, France
[6] Hop Bicetre, APHP Paris Saclay, Serv Endocrinol & Maladies Reprod, F-94270 Le Kremlin Bicetre, France
[7] CNRS, Ecole Polytech, Inst Polytech Paris, Lab Biol Structurale Cellule,BIOC, F-91128 Palaiseau, France
[8] Hop Univ Robert Debre, APHP Nord, Ctr Reference Maladies Endocriniennes Rares Croiss, Endocrinol Pediat, F-75019 Paris, France
[9] Univ Paris Cite, Fac Sante, UFR Med, F-75006 Paris, France
[10] CHU Robert Debre, Pediat Endocrinol Dept, 49,Blvd Serurier, F-75019 Paris, France
[11] Batiment Rech, Fac Med Paris Saclay, Inserm U1185, 63 rue Gabriel Peri, F-94276 Le Kremlin Bicetre, France
关键词
adrenal adenoma; glucocorticoid resistance syndrome; glucocorticoid receptor; NR3C1; gene; LIGAND-BINDING DOMAIN; MINERALOCORTICOID RECEPTOR; CORTISOL RESISTANCE; POINT MUTATION; ANTAGONISM; HEALTH; POTENT; MODE; LBD;
D O I
10.1093/ejendo/lvae031
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective: Glucocorticoid resistance is a rare endocrine disease caused by variants of the NR3C1 gene encoding the glucocorticoid receptor (GR). We identified a novel heterozygous variant (GR(R569Q)) in a patient with uncommon reversible glucocorticoid resistance syndrome. Methods: We performed ex vivo functional characterization of the variant in patient fibroblasts and in vitro through transient transfection in undifferentiated HEK 293T cells to assess transcriptional activity, affinity, and nuclear translocation. We studied the impact of the variant on the tertiary structure of the ligand-binding domain through 3D modeling. Results: The patient presented initially with an adrenal adenoma with mild autonomous cortisol secretion and undetectable adrenocorticotropin hormone (ACTH) levels. Six months after surgery, biological investigations showed elevated cortisol and ACTH (urinary free cortisol 114 mu g/24 h, ACTH 10.9 pmol/L) without clinical symptoms, evoking glucocorticoid resistance syndrome. Functional characterization of the GR(R569Q) showed decreased expression of target genes (in response to 100 nM cortisol: SGK1 control +97% vs patient +20%, P < .0001) and impaired nuclear translocation in patient fibroblasts compared to control. Similar observations were made in transiently transfected cells, but higher cortisol concentrations overcame glucocorticoid resistance. GRR569Q showed lower ligand affinity (Kd GRWT: 1.73 nM vs GR(R569Q): 4.61 nM). Tertiary structure modeling suggested a loss of hydrogen bonds between H3 and the H1-H3 loop. Conclusion: This is the first description of a reversible glucocorticoid resistance syndrome with effective negative feedback on corticotroph cells regarding increased plasma cortisol concentrations due to the development of mild autonomous cortisol secretion.
引用
收藏
页码:284 / 295
页数:12
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