ECE2017 Guided Posters Adrenal 1 (10 abstracts)
Identification of a new glucocorticoid receptor mutation underscores the substantial prevalence of genetic NR3C1 alterations in adrenal hyperplasia: the French National Research Program MUTA-GR
Géraldine Vitellius 1 , Brigitte Delemer 2 , Philippe Caron 3 , Antoine Bennet 3 , Jerome Bouligand 1, , Anne Guiochon-Mantel 1 , Say Viengchareun 1 , Christian Dani 6 , Severine Trabado 1, & Marc Lombes 1,
1Inserm UMR S 1185, Kremlin Bicetre, France; 2Service d’Endocrinologie, Hopital Robert Debré, CHU de Reims, REIMS, France; 3Service d’endocrinologie, maladies métabolique et nutrition,CHU Larrey, TOULOUSE, France; 4Service de Génétique moléculaire, pharmacogénétique et hormonologie, KREMLIN BICETRE, France; 5Service d’Endocrinologie et des Maladies de la Reproduction, KREMLIN BICETRE, France; 6Université Côte d’Azur, CNRS, Inserm, iBV, NICE, France.
Primary generalized glucocorticoid resistance is characterized by glucocorticoid excess without any Cushing syndrome. Patients exhibit variable clinical presentation including arterial hypertension, hirsutism or adrenal hyperplasia. Although glucocorticoid resistance has been associated with glucocorticoid receptor (GR) mutations (encoded by NR3C1 gene), only 23 mutations have been reported so far. We have conducted a French National Research Program, referred to as MUTA-GR that aims at determining the prevalence of NR3C1 genetic alterations in patients with adrenal masses associating by glucocorticoid resistance. In this context, we have recently identified a novel GR stop mutation in a 43-year-old man presenting with glucocorticoid resistance, bilateral adrenal hyperplasia and biological hypercortisolism (1.5 to 3-fold increased in 24 h urinary free cortisol, negative response to dexamethasone suppression test and normal plasma ACTH concentrations). Alteration of GR signaling is currently validated by transient transfection assays, binding studies, subcellular trafficking, Chromatin Imunoprecipitation experiments, stability investigation, three-dimensional modeling and gene expression studies.
More than 120 patients have been enrolled and five original GR heterozygous mutations (two missense and three false sense including R469X, R477S, Y478C, L672P) were discovered. Each original mutation impaired a different step of GR intracellular signaling. Ex vivo experiments performed on patients’ fibroblasts demonstrated that some mutations (R469X, R477S) led to an haploinsufficiency phenotype with a decreased response in glucocorticoid-dependent target gene expression (FKBP5, SGK1).
Interestingly, all mutated patients present with metabolic disorders (high BMI, metabolic syndrome, …), supporting the essential role played by glucocorticoid signaling in adipocyte physiology that we are currently exploring. Altogether, GR mutations are not such an uncommon event given that 5% of our patients carried NR3C1 alterations. Collectively, GR defects are not a rare cause of glucocorticoid resistance, an incidence initially minimized. We propose that genetic screening of the NR3C1 gene should be conducted in patients with adrenal incidentalomas and subclinical hypercorticism.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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