رسالة جامعية
Involvement of the Glucocorticoid Receptor in Human Disease ; Implication du récepteur des glucocorticoïdes en physiopathologie humaine
| العنوان: | Involvement of the Glucocorticoid Receptor in Human Disease ; Implication du récepteur des glucocorticoïdes en physiopathologie humaine |
|---|---|
| المؤلفون: | Vitellius, Géraldine |
| المساهمون: | Signalisation Hormonale, Physiopathologie Endocrinienne et Métabolique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Bicêtre AP-HP, Le Kremlin-Bicêtre, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Saclay (COmUE), Marc Lombes |
| المصدر: | https://theses.hal.science/tel-02957217Test ; Génétique humaine. Université Paris Saclay (COmUE), 2019. Français. ⟨NNT : 2019SACLS256⟩. |
| بيانات النشر: | HAL CCSD |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Glucocorticoid receptor, Nr3c1, GR loss-Of-Function mutation, Pseudohypermineralocorticism, Bilateral adrenal hyperplasia, Hsd11b2, Récepteur des glucocorticoides, Mutations inactivatrices du GR, Pseudohyperaldostéronisme, Hyperplasie bilatérale des surrénales, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism |
| الوصف: | Glucocorticoids (GC) regulate many essential biological functions by activating the glucocorticoid receptor (GR). GR loss-of function mutations are responsible for GC resistance syndrome, often associated with high blood pressure, hirsutism, bilateral adrenal hyperplasia (BAH) and obesity. Herein, functional characterization of 13 GR variants is presented (expression and binding studies, transactivation assays, subcellular localization) 6 variants were discovered with next-generating sequencing and had no functional impact on GR signaling while 7 GR loss-of-function mutations were mainly discovered during the National Clinical Hospital Research Program, Muta-GR. This PHRC discloses a 5% prevalence of GR loss-of-function mutations in a cohort of 100 patients with BAH, biological hypercortisolism and/or hypertension without Cushing signs. A GR haploinsuffisiency was demonstrated by a reduced dexamethasone-induced FKBP5 expression in skin fibroblasts of some patients harbouring GR loss-of-function mutations. These patients often presented with hypercorticism, hypokalemia, low renin and aldosterone levels, consistent with a pseudohypermineralocorticism. We showed that HSD11B2 encoding the 11β-HSD2 enzyme inactivating GC, is a direct GR target gene by transient transfection of reporter gene, RT-qPCR, LC/MSMS and ChIP. We failed to introduce GR loss-of-function mutations in human preadipocytes and adrenocortical cells by Crispr/Cas 9 technology. This work should facilitate selection of patients in whom GR mutation may be search, enabling an appropriate follow-up. ; Les glucocorticoïdes (GC), généralement sécrétés par le cortex surrénalien, exercent de très nombreuses fonctions dans l’organisme, via leur liaison au récepteur des glucocorticoïdes (GR). Les rares mutations inactivatrices du GR déjà décrites, sont responsables d’un syndrome de résistance aux GC et peuvent conduire à une hypertension artérielle (HTA), une hyperplasie surrénalienne (HBS), un hirsutisme et une obésité. Dans ce travail, nous avons caractérisé ... |
| نوع الوثيقة: | doctoral or postdoctoral thesis |
| اللغة: | French |
| العلاقة: | NNT: 2019SACLS256; tel-02957217; https://theses.hal.science/tel-02957217Test; https://theses.hal.science/tel-02957217/documentTest; https://theses.hal.science/tel-02957217/file/84888_VITELLIUS_2019_archivage.pdfTest |
| الإتاحة: | https://theses.hal.science/tel-02957217Test https://theses.hal.science/tel-02957217/documentTest https://theses.hal.science/tel-02957217/file/84888_VITELLIUS_2019_archivage.pdfTest |
| حقوق: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.B0BCD3AA |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |