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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

Pediatric and Reproductive Endocrinology Branch (E.C., T.K., T.I., A.T., K.Z., G.P.C.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Department of Endocrinology, Brigham and Women’s Hospital, Harvard Medical School (A.R.), Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Dr. Evangelia Charmandari, Department of Pediatric Endocrinology, Great Ormond Street Hospital for Children, 9th Floor, Southwood Building, Great Ormond Street, London, United Kingdom WC1N 3JH. E-mail: charmane{at}mail.nih.gov.

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- (hGR) 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 (TC) at nucleotide position 2318 (exon 9) of the hGR 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 hGRL773P mutant impaired glucocorticoid signal transduction. Compared with the wild-type hGR, hGRL773P 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 hGR is extremely important in conferring transactivational activity by altering multiple functions of this composite transcription factor.

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