A novel point mutation in the ligand-binding domain (LBD) of the human glucocorticoid receptor (hGR) causing generalized glucocorticoid resistance: the importance of the C terminus of hGR LBD in conferring transactivational activity.

C) at nucleotide position 2318 (exon 9) of the hGRalpha gene, which resulted in substitution of leucine by proline at amino acid position 773 in the ligand-binding domain of the receptor. We systematically investigated the molecular mechanisms through which the natural hGRalphaL773P mutant impaired glucocorticoid signal transduction. Compared with the wild-type hGRalpha, hGRalphaL773P demonstrated a 2-fold reduction in the ability to transactivate the glucocorticoid-inducible mouse mammary tumor virus promoter, exerted a dominant negative effect on the wild-type receptor, had a 2.6-fold reduction in the affinity for ligand, showed delayed nuclear translocation (30 vs. 12 min), and, although it preserved its ability to bind to DNA, displayed an abnormal interaction with the GR-interacting protein 1 coactivator in vitro. We conclude that the carboxyl terminus of the ligand-binding domain of hGRalpha is extremely important in conferring transactivational activity by altering multiple functions of this composite transcription factor. -->
Substance Nomenclature: 0 (DNA Primers)
0 (Glucocorticoids)
0 (Ligands)
0 (Receptors, Glucocorticoid)
7S5I7G3JQL (Dexamethasone)
VC2W18DGKR (Thymidine)
Entry Date(s): Date Created: 20050317 Date Completed: 20050705 Latest Revision: 20191210
Update Code: 20221213
DOI: 10.1210/jc.2004-1920
PMID: 15769988
Autor: Charmandari E; Department of Pediatric Endocrinology, Great Ormond Street Hospital for Children, 9th Floor, Southwood Building, Great Ormond Street, London, United Kingdom WC1N 3JH. charmane@mail.nih.gov, Raji A, Kino T, Ichijo T, Tiulpakov A, Zachman K, Chrousos GP
Jazyk: angličtina
Zdroj: The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2005 Jun; Vol. 90 (6), pp. 3696-705. Date of Electronic Publication: 2005 Mar 15.
DOI: 10.1210/jc.2004-1920
Abstrakt: Glucocorticoid resistance is a rare, familial or sporadic condition characterized by partial end-organ insensitivity to glucocorticoids. The clinical spectrum of the condition is broad, ranging from completely asymptomatic to severe hyperandrogenism and/or mineralocorticoid excess. The molecular basis of glucocorticoid resistance has been ascribed to mutations in the human glucocorticoid receptor-alpha (hGRalpha) gene, which impair one or more of the molecular mechanisms of GR action, thus altering tissue sensitivity to glucocorticoids. We identified a new case of generalized glucocorticoid resistance in a young woman who presented with a long-standing history of fatigue, anxiety, hyperandrogenism, and hypertension. The disease was caused by a novel, heterozygous mutation (T-->C) at nucleotide position 2318 (exon 9) of the hGRalpha gene, which resulted in substitution of leucine by proline at amino acid position 773 in the ligand-binding domain of the receptor. We systematically investigated the molecular mechanisms through which the natural hGRalphaL773P mutant impaired glucocorticoid signal transduction. Compared with the wild-type hGRalpha, hGRalphaL773P demonstrated a 2-fold reduction in the ability to transactivate the glucocorticoid-inducible mouse mammary tumor virus promoter, exerted a dominant negative effect on the wild-type receptor, had a 2.6-fold reduction in the affinity for ligand, showed delayed nuclear translocation (30 vs. 12 min), and, although it preserved its ability to bind to DNA, displayed an abnormal interaction with the GR-interacting protein 1 coactivator in vitro. We conclude that the carboxyl terminus of the ligand-binding domain of hGRalpha is extremely important in conferring transactivational activity by altering multiple functions of this composite transcription factor.
Databáze: MEDLINE
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