Natural Glucocorticoid Receptor Mutants Causing Generalized Glucocorticoid Resistance: Molecular Genotype, Genetic Transmission, and Clinical Phenotype

Abstract

Glucocorticoid resistance is a rare, familial, or sporadic condition characterized by partial end-organ insensitivity to glucocorticoids. The clinical spectrum of the condition ranges from completely asymptomatic to severe hyperandrogenism, fatigue, and/or mineralocorticoid excess. The molecular basis of glucocorticoid resistance in several families and sporadic cases has been ascribed to mutations in the human glucocorticoid receptor-alpha (hGRalpha) gene, which impair the ability of the receptor to transduce the glucocorticoid signal. We systematically investigated the molecular mechanisms through which natural, ligand-binding domain hGRalpha mutants, including hGRalphaI559N, hGRalphaV571A, hGRalphaD641V, hGRalphaV729I, and hGRalphaI747M, produce a defective signal and determined whether their differential effects on hGRalpha function might account for the type of genetic transmission of the disorder and the variable clinical phenotype of the affected subjects. Our findings suggest that all five mutant receptors studied have ligand-binding domains with decreased intrinsic transcriptional activity. Unlike hGRalphaI559N and I747M previously shown to exert a dominant negative effect upon the transcriptional activity of hGRalpha, hGRalphaV571A, D641V, and V729I do not have such an effect. All five mutants studied demonstrate varying degrees of decreased affinity for the ligand in a standard dexamethasone binding assay, but preserve their ability to bind DNA. The nondominant negative mutants, hGRalphaV571A, D641V, and V729I, show delayed translocation into the nucleus after exposure to ligand. Finally, hGRalphaI559N, V571A, D641V, and V729I display an abnormal interaction with the glucocorticoid receptor-interacting protein-1 coactivator in vitro, as this was previously shown also for hGRalphaI747M. We conclude that each of the above hGRalpha mutations imparts different functional defects upon the glucocorticoid signal transduction pathway, which explains the autosomal recessive or dominant transmission of the disorder, but might only explain in part its variable clinical phenotype.

Birthweight is associated with DNA promoter methylation of the glucocorticoid receptor in human placenta

“…27 Altered methylation of the GR in the placenta and subsequent dysregulated expression of the GR (and thereby altered glucocorticoid signaling) may lead to specific adult phenotypes, such as glucocorticoid resistance, as well as to increased risks of metabolic disorders, such as Type 2 diabetes and obesity. [28][29][30] To date, associations between placental GR methylation and adult metabolic outcomes have yet to be elucidated. Ke and colleagues demonstrated an increase in expression of some forms of GR in the hippocampus of IUGR rats.…”

Genotype–phenotype correlation in a family with primary cortisol resistance: possible modulating effect of the ER22/23EK polymorphism.

“…At present, five different mutations have been identified in five different kindreds: C1844T (V571A), A2054T (D641V), G2317A (V729I), T2373G (I747M), and a 4-bp deletion at the 3 0 boundary of exon 6. In addition, five more mutations were described in sporadic cases: G1430A (R477H), G2035A (G679S), T1808A (I559N), T2318C (L773P), and T2209C (F737L) (7)(8)(9)(10)(11)(12)(13). The genotype has been identified as either homozygous mutation with autosomal recessive or heterozygous mutation with autosomal dominant transmission in the familial cases.…”

Causas raras de pseudo-hermafroditismo feminino: quando suspeitar?

“…Os pacientes respondem muito bem ao tratamento com doses elevadas (1-3mg/dia) de dexametasona (49,52).…”

“…A base molecular da resistência generalizada familiar aos glicocorticóides está parcialmente elucidada (49,(51)(52)(53). Diferentes anormalidades funcionais no receptor de glicocorticóides (GR) têm sido detectadas nos indivíduos com SRGG, incluindo dimi-nuição da capacidade de ligação ao hormônio, diminuição do número de receptores, aumento da termolabilidade e diminuição da capacidade de ligação do GR ao DNA (48,55,56).…”