A Novel Point Mutation of the Human Glucocorticoid Receptor Gene Causes Primary Generalized Glucocorticoid Resistance Through Impaired Interaction With the LXXLL Motif of the p160 Coactivators: Dissociation of the Transactivating and Transreppressive Activities

Context: Primary generalized glucocorticoid resistance is a rare genetic disorder characterized by generalized, partial, target-tissue insensitivity to glucocorticoids. The molecular basis of the condition has been ascribed to inactivating mutations in the human glucocorticoid receptor (hGR) gene. Objective: The objective of the study was to present three new cases caused by a novel mutation in the hGR gene and to delineate the molecular mechanisms through which the mutant receptor impairs glucocorticoid signal transduction. Design and Results: The index case (father) and his two daughters presented with increased urinary free cortisol excretion and resistance of the hypothalamic-pituitary-adrenal axis to dexamethasone suppression in the absence of clinical manifestations suggestive of Cushing syndrome. All subjects harbored a novel, heterozygous, point mutation (T -> G) at nucleotide position 1724 of the hGR gene, which resulted in substitution of valine by glycine at amino acid 575 of the receptor. Compared with the wild-type receptor, the hGR alpha V575G demonstrated a significant (33%) reduction in its ability to transactivate the mouse mammary tumor virus promoter in response to dexamethasone, a 50% decrease in its affinity for the ligand, and a 2.5-fold delay in nuclear translocation. Although it did not exert a dominant negative effect on the wild-type receptor and preserved its ability to bind to DNA, hGR alpha V575G displayed significantly enhanced (similar to 80%) ability to transrepress the nuclear factor-kappa B signaling pathway. Finally, the mutant receptor hGR alpha V575G demonstrated impaired interaction with the LXXLL motif of the glucocorticoid receptor-interacting protein 1 coactivator in vitro and in computer-based structural simulation via its defective activation function-2 (AF-2) domain. Conclusions: The natural mutant receptor hGR alpha V575G causes primary generalized glucocorticoid resistance by affecting multiple steps in the glucocorticoid signaling cascade, including the affinity for the ligand, the time required for nuclear translocation, and the interaction with the glucocorticoid-interacting protein-1 coactivator

Re-thinking accountability measures for secondary school arts in England: lessons we could learn from New Zealand

This paper, a critical examination of educational concepts, policies and practices, presents findings from research into the impact of accountability agendas on teacher professionalism and pedagogic practices. The study, theoretically framed through Halstead’s (1994) notions of contractual and responsive accountability, and Gramsci’s (1971) hegemonic practices, examined secondary arts teachers’ pedagogical autonomy and professionalism in England and New Zealand. We provide an overview of current education policy contexts in both countries, and their impact upon secondary school arts education (years 11-16). Drawing from interview data from 15 England and New Zealand teachers we offer a critique and innovative counter-narrative for the accountability measures currently dominating English schooling. Drawing together perspectives from both jurisdictions, we suggest more inclusive, democratic and responsive assessment and performative measures for the English context

Glucocorticoid replacement therapy and vertebral fractures in hypopituitary adult males with GH deficiency

Objective: GH deficiency (GHD) and glucocorticoid excess are associated with increased risk of fragility fractures. We aimed to evaluate whether the prevalence of vertebral fractures may be influenced by glucocorticoid over-replacement in hypopituitary males with GHD. Design: Cross-sectional study. Methods: Fifty-one adult hypopituitary patients (all males; mean age 55 years, range: 23-81) with severe adult-onset GHD (replaced in 21 patients and untreated in 30 patients) and glucocorticoid deficiency on replacement treatment were studied for vertebral fractures using a radiological and morphometric approach. Results: Vertebral fractures were observed in 31 patients (60.8%) in correlation with untreated GHD, urinary cortisol values, and cortisone doses. Patients were stratified according to treatment of GHD, and current and cumulative cortisone doses. In untreated GHD, vertebral fractures occurred more frequently in patients who had received higher (greater than median) cumulative and current doses of cortisone compared with patients who had received lower (less than median) drug doses (95.2 vs 50.0%, P=0.009 and 90.5 vs 55.6%, P=0.04 respectively). In untreated GHD, fractured patients had significantly higher urinary cortisol values compared with patients without vertebral fractures (84 \u3bcg/24 h, range: 24-135 vs 49 \u3bcg/24 h, range: 30-96; P=0.04). In treated GHD patients, by contrast, the prevalence of vertebral fractures was not influenced by cumulative and current cortisone doses and urinary cortisol values. Conclusions: Glucocorticoid over-replacement may increase the prevalence of vertebral fractures in patients with untreated GHD. However, treatment of GHD seems to protect the skeleton from the deleterious effects of glucocorticoid overtreatment in hypopituitary patients. \ua9 2010 European Society of Endocrinology