Novel insights into the molecular mechanisms underlying generalized glucocorticoid resistance and hypersensitivity syndromes

摘要

Glucocorticoids play a fundamental role in many physiologic functions and contribute substantiallyto the achievement of homeostasis. These pleiotropic glucocorticoid actions are mediated bya ubiquitously expressed transcription factor, the human glucocorticoid receptor (hGR), whichmay influence the transcription rate of numerous target genes, interact with other transcriptionfactors, trigger the activation of several kinase pathways or modulate mitochondrial DNAexpression. Any genetic defects in the NR3C1 gene that encodes the hGR may cause PrimaryGeneralized Glucocorticoid Resistance or Hypersensitivity Syndromes, two rare allostatic endocrinologicconditions characterized by partial impaired tissue sensitivity to glucocorticoids.However, there are patients who present with clinical manifestations suggestive of the abovesyndromes and do not harbor an inactivating or activating point mutation, insertion or deletionin the NR3C1 gene. In these cases, several other factors might influence the glucocorticoidsignal transduction. In this review, we discuss the numerous glucocorticoid functions and themultiple hGR isoforms, we present the genomic, nongenomic and mitochondrial glucocorticoidsignaling cascade and we summarize the clinical manifestations and pathogenesis of PrimaryGeneralized Glucocorticoid Resistance or Hypersensitivity Syndromes. Finally, we speculatethat the next generation sequencing technologies will undoubtedly enable us to gain a deeperunderstanding of the GR “interactome”.