107 research outputs found
Familial Glucocorticoid Receptor Haploinsufficiency by Non-Sense Mediated mRNA Decay, Adrenal Hyperplasia and Apparent Mineralocorticoid Excess
Primary glucocorticoid resistance (OMIM 138040) is a rare hereditary disease that causes a generalized partial insensitivity to glucocorticoid action, due to genetic alterations of the glucocorticoid receptor (GR). Investigation of adrenal incidentalomas led to the discovery of a family (eight affected individuals spanning three generations), prone to cortisol resistance, bilateral adrenal hyperplasia, arterial hypertension and hypokalemia. This phenotype exacerbated over time, cosegregates with the first heterozygous nonsense mutation p.R469[R,X] reported to date for the GR, replacing an arginine (CGA) by a stop (TGA) at amino-acid 469 in the second zinc finger of the DNA-binding domain of the receptor. In vitro, this mutation leads to a truncated 50-kDa GR lacking hormone and DNA binding capacity, devoid of hormone-dependent nuclear translocation and transactivation properties. In the proband's fibroblasts, we provided evidence for the lack of expression of the defective allele in vivo. The absence of detectable mutated GR mRNA was accompanied by a 50% reduction in wild type GR transcript and protein. This reduced GR expression leads to a significantly below-normal induction of glucocorticoid-induced target genes, FKBP5 in fibroblasts. We demonstrated that the molecular mechanisms of glucocorticoid signaling dysfunction involved GR haploinsufficiency due to the selective degradation of the mutated GR transcript through a nonsense-mediated mRNA Decay that was experimentally validated on emetine-treated propositus' fibroblasts. GR haploinsufficiency leads to hypertension due to illicit occupation of renal mineralocorticoid receptor by elevated cortisol rather than to increased mineralocorticoid production reported in primary glucocorticoid resistance. Indeed, apparent mineralocorticoid excess was demonstrated by a decrease in urinary tetrahydrocortisone-tetrahydrocortisol ratio in affected patients, revealing reduced glucocorticoid degradation by renal activity of the 11β-hydroxysteroid dehydrogenase type 2, a GR regulated gene. We propose thus that GR haploinsufficiency compromises glucocorticoid sensitivity and may represent a novel genetic cause of subclinical hypercortisolism, incidentally revealed bilateral adrenal hyperplasia and mineralocorticoid-independent hypertension
Etude du syndrome de Cuching au cours des néoplasies endocriniennes multiples de type I
REIMS-BU Santé (514542104) / SudocSudocFranceF
Acromégalie dans le départements Marne-Ardennes de 1993 à 2002. Incidence de la maladie et de ses complications néoplasiques
REIMS-BU Santé (514542104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF
Comment sont suivis les jeunes adultes diabétiques de type 1 non pris en charge par le secteur d endocrinologie adulte ? Quelles sont les spécificités de cette prise en charge pour le médecin traitant ? Analyse d une cohorte au CHU de Reims
REIMS-BU Santé (514542104) / SudocSudocFranceF
Prolactinomes et grossesse
REIMS-BU Santé (514542104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF
Analogues du GLP-1 et insuline chez le patient diabétique de type 2 obèse (association ou Switch ? Impacts pondéral et métabolique)
REIMS-BU Santé (514542104) / SudocSudocFranceF
L'apnée du sommeil : une conséquence grave de l'acromégalie. Etude d'une série de patients acromégales, collaboration entre le CHU de Reims et le CHRU de Lille
REIMS-BU Santé (514542104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF
Le diabète dans l'acromégalie : prévalence, facteurs de risque et description à partir du registre national de l'acromégalie et la série Champagne-Ardenne
REIMS-BU Santé (514542104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF
Intérêts du dosage de l'ACTH au cours du cathétérisme des sinus petreux dans le syndrome de Cuching
REIMS-BU Santé (514542104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF
Etude médico-sociale de la population diabétique en hospitalisation de semaine au Centre Hospitalier Universitaire de Reims
REIMS-BU Santé (514542104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF
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