A novel point mutation in helix 11 of the ligand-binding domain of the human glucocorticoid receptor gene causing generalized glucocorticoid resistance

Evangelia Charmandari, Tomoshige Kino, Takamasa Ichijo, William Jubiz, Liliana Mejia, Keith Zachman, George P. Chrousos

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Abstract

Background: Generalized glucocorticoid resistance is a rare condition characterized by partial, end-organ insensitivity to glucocorticoids, compensatory elevations in adrenocorticotropic hormone and cortisol secretion, and increased production of adrenal steroids with androgenic and/or mineralocorticoid activity. We have identified a new case of glucocorticoid resistance caused by a novel mutation of the human glucocorticoid receptor (hGR) gene and studied the molecular mechanisms through which the mutant receptor impairs glucocorticoid signal transduction. Methods and Results: We identified a novel, single, heterozygous nucleotide (T→C) substitution at position 2209 (exon 9α) of the hGR gene, which resulted in phenylalanine (F) to leucine (L) substitution at amino acid position 737 within helix 11 of the ligand-binding domain of the protein. Compared with the wild-type receptor, the mutant receptor hGRαF737L demonstrated a significant ligand-exposure time-dependent decrease in its ability to transactivate the glucocorticoid- inducible mouse mammary tumor virus promoter in response to dexamethasone and displayed a 2-fold reduction in the affinity for ligand, a 12-fold delay in nuclear translocation, and an abnormal interaction with the glucocorticoid receptor-interacting protein 1 coactivator. The mutant receptor preserved its ability to bind to DNA and exerted a dominant-negative effect on the wild-type hGRα only after a short duration of exposure to the ligand. Conclusions: The mutant receptor hGRαF737L causes generalized glucocorticoid resistance because of decreased affinity for the ligand, marked delay in nuclear translocation, and/or abnormal interaction with the glucocorticoid receptor-interacting protein 1 coactivator. These findings confirm the importance of the C terminus of the ligand-binding domain of the receptor in conferring transactivational activity.

Original languageEnglish
Pages (from-to)3986-3990
Number of pages5
JournalJournal of Clinical Endocrinology and Metabolism
Volume92
Issue number10
DOIs
Publication statusPublished - Oct 2007
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

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