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

Section on Pediatric Endocrinology (E.C., T.K., T.I., K.Z., G.P.C.), Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; First Department of Pediatrics (G.P.C.), Athens University Medical School, Athens 11527, Greece; and Centro de Endocrinologia (W.J., L.M.), Metabolismo y Diabetes and Clinica, Fundacion Valle del Lili, Cali, Colombia

Address all correspondence and requests for reprints to: Evangelia Charmandari, M.D., Section on Endocrinology and Metabolism, Foundation for Biomedical Research of the Academy of Athens, 4 Soranou Efessiou, Athens 11527, Greece. E-mail: evangelia.charmandari{at}googlemail.com.

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 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 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 hGR only after 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 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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				E. Charmandari, T. Ichijo, W. Jubiz, S. Baid, K. Zachman, G. P. Chrousos, and T. Kino A Novel Point Mutation in the Amino Terminal Domain of the Human Glucocorticoid Receptor (hGR) Gene Enhancing hGR-Mediated Gene Expression J. Clin. Endocrinol. Metab., December 1, 2008; 93(12): 4963 - 4968. [Abstract] [Full Text] [PDF]

				E. Charmandari, T. Kino, T. Ichijo, and G. P. Chrousos Generalized Glucocorticoid Resistance: Clinical Aspects, Molecular Mechanisms, and Implications of a Rare Genetic Disorder J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1563 - 1572. [Abstract] [Full Text] [PDF]