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-Results: We identified a novel, single, heterozygous nucleotide (T C) substitution at position 2209 (exon 9) 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 hGRF737L demonstrated a significant ligand-exposure time-dependent decrease in its ability to transactivate the glucocorticoid-inducible MMTV 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 (GRIP1) coactivator. The mutant receptor preserved its ability to bind to DNA and exerted a dominant negative effect upon the wild-type hGR only following a short duration of exposure to the ligand.

Conclusions: The mutant receptor hGRF737L causes generalized glucocorticoid resistance because of decreased affinity for the ligand, marked delay in nuclear translocation and/or abnormal interaction with the GRIP1 coactivator. These findings confirm the importance of the C-terminus of the ligand binding domain of the receptor in conferring transactivational activity.