title: Recent advances in the molecular mechanisms causing primary generalized glucocorticoid resistance.
abstract: Primary Generalized Glucocorticoid Resistance is a rare condition characterized by generalized, partial, target tissue insensitivity to glucocorticoids owing to inactivating mutations, insertions or deletions in the human glucocorticoid receptor (hGR) gene (NR3C1). Recent advances in molecular and structural biology have enabled us to elucidate the molecular mechanisms of action of the mutant receptors and to understand how certain conformational alterations of the defective hGRs result in generalized glucocorticoid resistance. Furthermore, our ever-increasing understanding of the molecular mechanisms of glucocorticoid action indicates that the glucocorticoid signaling pathway is a stochastic system that plays a fundamental role in maintaining both basal and stress-related homeostasis. In this review, we summarize the clinical manifestations and molecular pathogenesis of Primary Generalized Glucocorticoid Resistance, we present our recent findings from the functional characterization of three novel heterozygous point mutations in the NR3C1 gene, and we discuss the diagnostic approach and therapeutic management of the condition. When the condition is suspected, we recommend sequencing analysis of the NR3C1 gene as well as of other genes encoding proteins involved in the glucocorticoid signal transduction. The tremendous progress of next-generation sequencing will undoubtedly uncover novel hGR partners or cofactors.
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens Medical School, "Aghia Sophia" Children's Hospital, Division of Endocrinology and Metabolism, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Nicolaides
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece.
authors.forename: Agaristi
authors.initials: A
authors.lastname: Lamprokostopoulou
authors.affiliation: Division of Endocrinology and Metabolism, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Amalia
authors.initials: A
authors.lastname: Sertedaki
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, University of Athens Medical School, "Aghia Sophia" Children's Hospital, Division of Endocrinology and Metabolism, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Charmandari
mesh_terms: D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid