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 everincreasing 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.

Epidermal glucocorticoid and mineralocorticoid receptors act cooperatively to regulate epidermal development and counteract skin inflammation

“…GC synthesis in the adrenal cortex is controlled by the hypothalamic–pituitary–adrenal (HPA) axis 10 . GCs exert their effects through binding to the GC receptor (GR) and the mineralocorticoid receptor (MR), structurally and functionally homologous ligand-activated transcription factors 1 , 11 – 13 .…”

“…Importantly, MR has a 10-fold higher affinity for GCs than GR. Expression of the GC-inactivating enzyme 11-beta hydroxysteroid dehydrogenase (HSD11B) type 2 in tissues such as kidney and heart protects MR from constant GC occupation and allows activation by aldosterone, which has key roles in electrolyte balance 10 , 13 . In these tissues, MR activation is involved in pathophysiological effects ultimately leading to inflammation and fibrosis and MR antagonists are beneficial for patients with cardiovascular and renal disease 19 .…”

Glucocorticoid Receptor Signaling in Skin Barrier Function

“…The importance of appropriate GC levels for normal tissue function is clearly illustrated in extreme situations of hormone imbalances where chronic excess or deficiency leads to pathological conditions, such as Cushing's or Addison's disease, respectively [1]. In both scenarios, dysfunctional responses to this hormone can result in differential tissue sensitivity and manifest as clinical GC resistance (e.g., primary generalized glucocorticoid resistance) or hypersensitivity [27]. Remarkably, cutaneous abnormalities in Cushing's patients-skin atrophy, increased fragility and easy bruising, elevated infection risk, and impaired wound healing-are very similar to those found in aging and also after long-term/high-dose GC pharmacological treatments [28,29].…”

Novel role for receptor dimerization in post-translational processing and turnover of the GRα

“…In short, disruptions in GRα function, are known to modulate the subcellular localization, ligand binding, and transactivation ability of the receptor, and are regulated by, amongst others, increases in additional GR isoforms (GRβ and GRγ) due to alternative splicing events, inactivating GRα mutations, the inflammatory cytokine profile of the cellular microenvironment and mutations/polymorphisms in the ERK pathway, as eloquently reviewed by Nicolaides et al . 17 , Oakley et al . 6 , 18 , and Patel et al .…”

“… 19 . In some cases GC resistance is inherited and is frequently associated with alterations at the level of GRα function, caused by inactivating mutations 17 . However, more common is the development of an acquired GC resistance, often linked to disease-progression 20 – 22 or prolonged GC treatment 23 – 25 , which reduces the level of the GR protein pool 26 .…”