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Case Reports
. 2007 Oct;92(10):3986-90.
doi: 10.1210/jc.2006-2830. Epub 2007 Jul 17.

A Novel Point Mutation in Helix 11 of the Ligand-Binding Domain of the Human Glucocorticoid Receptor Gene Causing Generalized Glucocorticoid Resistance

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Case Reports

A Novel Point Mutation in Helix 11 of the Ligand-Binding Domain of the Human Glucocorticoid Receptor Gene Causing Generalized Glucocorticoid Resistance

Evangelia Charmandari et al. J Clin Endocrinol Metab. .

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 9alpha) 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 hGRalphaF737L 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 hGRalpha only after a short duration of exposure to the ligand.

Conclusions: The mutant receptor hGRalphaF737L 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.

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