Novel causes of generalized glucocorticoid resistance.

Glucocorticoid resistance is a rare condition characterized by generalized, partial, target-tissue insensitivity to glucocorticoids. Compensatory elevations in circulating adrenocorticotropic hormone (ACTH) concentrations lead to increased secretion of cortisol and adrenal steroids with mineralocorticoid and/or androgenic activity, but no clinical evidence of hypercortisolism. The clinical spectrum of the condition is broad, ranging from asymptomatic to severe cases of hyperandrogenism, fatigue and/or mineralocorticoid excess. The molecular basis of glucocorticoid resistance has been ascribed to mutations in the human glucocorticoid receptor (hGR) gene, which impair glucocorticoid signal transduction, thereby altering tissue sensitivity to glucocorticoids. The study of functional defects of natural hGR mutants enhances our understanding of the molecular mechanisms of hGR action and highlights the importance of integrated cellular and molecular signaling mechanisms for maintaining homeostasis and preserving normal physiology.     

Glucocorticoid resistance

Glucocorticoids contribute fundame ntally to the maintenance of basal and stress-related homeostasis in all higher organisms. The major roles of these steroids in physiology are amply matched by their remarkable contributions to pathology. Glucocorticoid resistance is a rare familial, or sporadic condition characterized by partial end-organ insensitivity to glucocorticoids. The molecular basis of glucocorticoid resistance in several families and sporadic cases has been ascribed to mutations in the human glucocorticoid receptor α (hGRα) gene, which impair the ability of the receptor to transduce the glucocorticoid signal. Glucocorticoids are crucial for life, and therefore complete glucocorticoid resistance is uncommon. The purpose of this review is to discuss the many structural and functional features of the glucocorticoid receptor and also to evaluate the main clinical and laboratory characteristics of cortisol resistance. Published in Russian in Biokhimiyo, 2006, Vol. 71, No. 10, pp. 1328–1337.     

The analysis of the factors influencing the development of glucocorticoid resistance in the etiopathogenesis of severe bronchial asthma

Bronchial asthma is a disease of multi - factored etiology. Current data show that multiple genes may be involved in the pathogenesis of asthma. Corticosteroids (GCS) are the most effective anti-inflammatory therapy for inflammatory disease such as bronchial asthma. There are 2 major types of GCS-resistant asthma to treatment of high doses of inhaled and oral glucocorticoids. Type I GCS-resistant asthma is cytokine-induced or acquired. Type II GCS resistance involves generalized primary cortisol resistance, which affects all tissues and is likely associated with a mutation in the GCR gene or in genes that modulate GCR function. There are clear examples of glucocorticoid gene h-GCR/NR3C1 polymorphisms that can influence responses and sensitivity to glucocorticosteroids. This article may lead to holistic the development analysis of the factors determining the progress of the glucocorticoid resistance in the severe bronchial asthma with special acknowledgement of the influence of polymorphisms of the glucocorticoid receptor gene h-GCR/NR3C1 to formation GCS resistance.     

Lack of association between five polymorphisms in the human glucocorticoid receptor gene and glucocorticoid resistance

Glucocorticoid resistance due to mutations in the gene for the glucocorticoid receptor has been suggested to be more common than is thought at present, owing to the relative mildness of its symptoms and the difficulty of its diagnosis. To investigate the prevalence of mutations in the glucocorticoid receptor gene responsible for relative insensitivity to glucocorticoids, we carried out polymerase chain reaction/single-strand conformation analysis of the glucocorticoid receptor gene in a group of 20, otherwise healthy, persons with a reduced response in a dexamethasone suppression test and in 20 controls. We did not find mutations or polymorphisms associated with a reduced sensitivity to glucocorticoids. However, we identified five novel polymorphisms in the gene for the human glucocorticoid receptor, which may be useful in analyzing whether loss of (part of) the glucocorticoid receptor gene plays a role in glucocorticoid-resistant malignancies. Although relative resistance to glucocorticoids seems to be rather frequent in otherwise healthy persons, it is not usually associated with mutations or polymorphisms in the glucocorticoid receptor gene. Received: 17 July 1996 / Revised: 26 November 1996     

A gradient of glucocorticoid sensitivity among helper T cell cytokines

Helper T (Th) cells secret specific cytokines that promote immune responses whereas glucocorticoids limit the extent of immune responses by inhibiting cytokine secretion and other functions of Th cells. However, glucocorticoid resistance develops in subgroups of patients with Th cell-driven diseases such as asthma and Crohn’s disease. Recent evidence supports that Th1, Th2, and Th17 cells have distinct glucocorticoid sensitivity. Th1 cells are sensitive to glucocorticoid-induced apoptosis and cytokine suppression while Th2 cells are sensitive to the latter but not the former and Th17 cells are resistant to both. This gradient of glucocorticoid sensitivity of Th cells corresponds to the glucocorticoid sensitivity of the diseases they underlie. We identify the mechanisms contributing to distinct glucocorticoid sensitivity of Th cells and their cytokines in the literature, as this information is useful to improve treatment strategies for glucocorticoid resistant immunological disorders.     

Genetic variations of the NR3C1 gene in children with sporadic nephrotic syndrome

Previous studies have demonstrated that the genetic variations of glucocorticoid receptor gene (NR3C1) are associated with both familial steroid resistance and acquired steroid resistance in some diseases, such as Cushing's disease, leukemia, lupus nephritis, and female pseudohermaphroditism. In this study, we examined the genetic variations of NR3C1 in 35 children with sporadic steroid-resistant nephrotic syndrome (SRNS), and in 83 cases with sporadic steroid-sensitive NS (SSNS) using polymerase chain reaction, denaturing high-performance liquid chromatography and DNA sequencing, and analyzed possible associations between NR3C1 variants and steroid resistance in sporadic NS. No causative mutations were found; however, six previously identified and six novel polymorphisms, 1206C > T, 1374A > G, 2382C > T, 2193T > G, IVS7-68_-63delAAAAAA, and IVS8-9C > G, were detected. Two novel haplotypes, [1374A > G; IVS7-68_-63delAAAAAA; IVS8-9C > G; 2382C > T] and [1896C > T; 2166C > T; 2430T > C], of NR3C1 were also identified in sporadic NS and controls. The odds ratios (95% Confidence Interval) for the two novel NR3C1 haplotypes in the sporadic nephrotic children at risk of steroid resistance were 4.970 (0.889-27.788) and 2.194 (0.764-6.306), respectively, but the association between NR3C1 haplotypes and steroid resistance was not significant. Further studies on the possible association between the two novel NR3C1 haplotypes and steroid resistance in sporadic NS in larger cohorts are required.     

Mechanisms of brain glucocorticoid resistance in stress-induced psychopathologies

Exposure to stress activates the hypothalamic–pituitary–adrenal axis and leads to increased levels of glucocorticoid (GC) hormones. Prolonged elevation of GC levels causes neuronal dysfunction, decreases the density of synapses, and impairs neuronal plasticity. Decreased sensitivity to glucocorticoids (glucocorticoid resistance) that develops as a result of chronic stress is one of the characteristic features of stress-induced psychopathologies. In this article, we reviewed the published data on proposed molecular mechanisms that contribute to the development of glucocorticoid resistance in brain, including changes in the expression of the glucocorticoid receptor (GR) gene, biosynthesis of GR isoforms, and GR posttranslational modifications. We also present data on alterations in the expression of the FKBP5 gene encoding the main component of cell ultra-short negative feedback loop of GC signaling regulation. Recent discoveries on stressand GRinduced changes in epigenetic modification patterns as well as normalizing action of antidepressants are discussed. GR and FKBP5 gene polymorphisms associated with stress-induced psychopathologies are described, and their role in glucocorticoid resistance is discussed.     

Glucocorticoid receptor gene polymorphisms in premenopausal women with major depression.

Glucocorticoid receptor gene polymorphisms are associated with glucocorticoid hypersensitivity and visceral obesity. Perturbations in HPA axis sensitivity to glucocorticoids implicated in the pathogenesis of major depression may result from functional alterations in the glucocorticoid receptor gene. We 1) examined the prevalence of genotype distribution of specific polymorphisms of the glucocorticoid receptor gene (Bcl1, N363S, rs33388, rs33389) in a subset of women from the P.O.W.E.R. Study (which enrolled 21- to 45-year-old premenopausal women with major depression and healthy controls) and 2) explored whether such polymorphisms were associated with visceral obesity and insulin resistance. Women with major depression had a higher body mass index, a higher waist:hip ratio, and more body fat than did controls. No differences were observed in plasma and urinary cortisol or in insulin sensitivity. The G/G genotype of the Bcl1 polymorphism was significantly more common (p<0.03) in women with major depression (n=52) than in controls (n=29). In addition, GG homozygotes (depressed n=10; controls n=2) had higher waist:hip ratios than did non-GG carriers (p<0.02). N363S, rs33388, and rs33389 polymorphisms were not different between groups. In conclusion, premenopausal women with both major depression and the GG genotype of the Bcl1 polymorphism had greater abdominal obesity compared with non-GG carriers.     

Alzheimer disease fibroblasts are hypersensitive to the lethal effects of a DNA-damaging chemical

A group of fibroblast lines from three patients with the sporadic form of Alzheimer disease (AD) showed a small but statistically significant hypersensitivity to the lethal effects of the DNA-damaging chemical N-methyl-N'-nitro-nitrosoguanidine (MNNG) when compared with lines from eight normal control subjects. A fibroblast line from a patient with a dominantly inherited form of familial AD had a hypersensitivity similar to that of the three sporadic AD lines. However, fibroblast lines from a group of five patients with spinal muscular atrophy (SMA) were not hypersensitive to the chemical, demonstrating that not every primary neuronal degeneration manifests hypersensitivity to this chemical. These findings are consistent with the possibility that a defect in DNA-repair mechanisms may be the cause of the in vitro hypersensitivity, as well as the premature death of neurons in vivo, in both the sporadic and familial forms of AD.     

Genetic Forms of Adrenal Insufficiency

Objective: The American Association of Clinical Endocrinologists Adrenal Scientific Committee has developed a series of articles to update members on the genetics of adrenal diseases.Methods: Case presentation, discussion of literature, table, and bullet point conclusions.Results: The genetic mutations associated with several familial causes of adrenal insufficiency have now been identified. The most common ones that will be discussed here include Allgrove syndrome, adrenoleukodystrophy, adrenal hypoplasia congenita, autoimmune polyglandular syndrome type 1, congenital adrenal hyperplasia (CAH), lipoid CAH, and familial glucocorticoid deficiency. Although these diseases most commonly present in childhood, some rarely present in adulthood, and thus all endocrinologists must be familiar with these syndromes. Some patients only develop glucocorticoid deficiency, and others have both glucocorticoid and mineralocorticoid deficiency. These diseases may be associated with other conditions, especially neurologic disease, hypogonadism, or dermatologic problems. Diagnosis is suspected based on clinical presentation and laboratory findings. Gene testing may be necessary for confirmation of a diagnosis and/or screening of family members.Conclusion: This article briefly reviews the various familial adrenal insufficiency syndromes and the specific associated gene defects.Abbreviations: AAA = Allgrove syndrome (alachrima-achalasiaadrenal insufficiency) ACTH = adrenocorticotropic hormone AHC = adrenal hypoplasia congenita ALD = adrenoleukodystrophy CAH = congenital adrenal hyperplasia DAX1 = dosage-sensitive sex reversal, adrenal hypoplasia congenita, X-chromosome FGD = familial glucocorticoid deficiency LCAH = lipoid CAH MCM4 = mini-chromosome maintenancedeficient 4 SF1 = steroidogenic factor 1 VLCFA = very-long-chain fatty acid     

Polymorphisms in the glucocorticoid receptor gene that modulate glucocorticoid sensitivity are associated with rheumatoid arthritis

Introduction  

The glucocorticoid receptor (GR) plays an important regulatory role in the immune system. Four polymorphisms in the GR gene are associated with differences in glucocorticoid (GC) sensitivity; the minor alleles of the polymorphisms N363 S and BclI are associated with relative hypersensitivity to GCs, while those of the polymorphisms ER22/23EK and 9β are associated with relative GC resistance. Because differences in GC sensitivity may influence immune effector functions, we examined whether these polymorphisms are associated with the susceptibility to develop Rheumatoid Arthritis (RA) and RA disease severity.     

The zebrafish as an in vivo model system for glucocorticoid resistance

Glucocorticoids regulate a wide range of systems in vertebrate organisms, and their effects are mediated by the glucocorticoid receptor (GR). The responsiveness to glucocorticoids differs largely between individuals. Resistance to glucocorticoids is an important medical problem, since it limits the efficacy of glucocorticoids when they are used to treat immune-related diseases like asthma and rheumatoid arthritis. Glucocorticoid resistance also contributes to the pathogenesis of other diseases, like major depression because of the decreased negative feedback on the hypothalamic pituitary adrenal axis. In this review, we present the zebrafish as an excellent in vivo model system to study glucocorticoid resistance. First, the zebrafish is the only non-primate animal model in which a β-isoform of GR occurs, which is a splice variant with dominant-negative activity. Zebrafish are easily genetically modified, so the expression of GRβ can be varied, creating an in vivo model for GRβ-induced glucocorticoid resistance. Second, by performing a forward-genetic screen using the glucocorticoid-induced decrease in POMC expression in the pituitary gland as a readout, several zebrafish mutants have been obtained which appear to be resistant to glucocorticoid treatment. We present here two types of in vivo models for studying glucocorticoid resistance, that will be used to study the molecular mechanism of glucocorticoid signaling and resistance. Finally these models will be used to screen for small molecules that can alleviate glucocorticoid resistance.     

Association between birth weight in preterm neonates and the BclI polymorphism of the glucocorticoid receptor gene

Endogenous and exogenous glucocorticoids influence fetal growth and development, and maternal administration of synthetic glucocorticoids may decrease the risk of perinatal morbidity including lung disease in preterm neonates. Because polymorphisms of the glucocorticoid receptor gene are known to influence the sensitivity to glucocorticoids, in the present study we examined whether any associations could exist among the BclI, N363S and ER22/23EK polymorphisms of the glucocorticoid receptor gene and gestational age, birth weight and/or perinatal morbidity of 125 preterm neonates born at 28-35 weeks' gestation with (n=57) or without maternal dexamethasone treatment (n=68). The prevalence of the three polymorphisms in the whole group of preterm infants was similar to that reported in healthy adult Hungarian population. However, we found that the BclI polymorphism significantly associated with higher birth weight adjusted for the gestational age (p=0.004, ANOVA analysis). None of the three polymorphisms showed an association with perinatal morbidities, including necrotizing enterocolitis, intraventricular hemorrhagia, patent ductus arteriosus, respiratory distress syndrome, bronchopulmonary dysplasia and sepsis in the two groups of preterm neonates with and without maternal dexamethasone treatment. These results suggest that the BclI polymorphism of the glucocorticoid receptor gene may have an impact on gestational age-adjusted birth weight, but it does not influence perinatal morbidities of preterm neonates.