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

Evangelia Charmandari, Annaswamy Raji, Tomoshige Kino, Takamasa Ichijo, Anatoly Tiulpakov, Keith Zachman, George P. Chrousos

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Abstract

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-α(hGRα) 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 hGRα 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 hGRαL773P mutant impaired glucocorticoid signal transduction. Compared with the wild-type hGRα, hGRαL773P 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 hGRα is extremely important in conferring transactivational activity by altering multiple functions of this composite transcription factor.

Original languageEnglish
Pages (from-to)3696-3705
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume90
Issue number6
DOIs
Publication statusPublished - Jun 2005
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

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