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

Koper, J. W.; Stolk, Ronald P.; deLange, P; Huizenga, N. A. T. M.; Molijn, G. J.; Hap., Pols; Grobbee, D. E.; Karl, Michael; deJong, F.H.; Brinkmann, A.O.; Lamberts, S. W. J.

doi:10.1007/s004390050425

Cited by 209 publications

(178 citation statements)

References 26 publications

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“…Recent data, however, suggest that relative glucocorticoid resistance caused by GR mutations may not be as infrequent as previously thought (Koper et al 1997). Thus, it seems pertinent to study whether psychiatric syndromes are more prevalent in patients with GR resistance and also whether such mutations may occur among psychiatric patients with dysregulation of the HPA system.…”

Section: Genetic Studiesmentioning

confidence: 76%

The Corticosteroid Receptor Hypothesis of Depression

Holsboer

2000

Neuropsychopharmacology

1,982

1,228

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Clinical EvidenceUntil now, the serendipitous discovery of antidepressants in the 1950s has profoundly inspired hypotheses of the pathogenesis of depression. The well-known pharmacological effects of antidepressants on presynaptic uptake transporters and degradating enzymes (i.e., MAO) of serotonin and norepinephrine has focused research on causality and treatment of depression on the metabolism of functional biogenic amines and the capacity of their respective receptors to alter intracellular signaling pathways that ultimately induce changes in gene activity. Elevated circulating levels of stress hormones among depressives were recognized even before antidepressants were discovered, but these changes were seen as epiphenomena, reflecting the stressful experience of depression, although M. Bleuler (1919) already demonstrated that hormones have diverse psychotropic effects and suggested hormone treatments as potential antidepressants. A vast amount of evidence has accumulated, that reject the view that altered stress hormone secretions in depression are epiphenomenal. During the past decade, several research groups formulated a hypothesis relating aberrant stress hormone dysregulation to causality of depression and submitted that antidepressants may act through normalisation of these HPA changes (

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Section: Genetic Studiesmentioning

confidence: 76%

The Corticosteroid Receptor Hypothesis of Depression

Holsboer

2000

Neuropsychopharmacology

1,982

1,228

View full text Add to dashboard Cite

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“…Excluding occasional sequence alterations introduced by the Taq polymerase, two types of clones could be distinguished ( Figure 1). One of these clones corresponded to the human GR wild-type sequence, 24 differing only in a known silent polymorphism in codon 766 (AAT-AAC), 25 the other differed by a missense mutation in codon 477 (CGC-CAC), leading to an arginine (R)-histidine (H) exchange. To verify the presence of this productive mutation, we amplified genomic DNA encompassing exon 4 and subjected it to bulk sequencing.…”

Section: Resultsmentioning

confidence: 99%

Glucocorticoid receptor heterozygosity combined with lack of receptor auto-induction causes glucocorticoid resistance in Jurkat acute lymphoblastic leukemia cells

et al. 2004

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Glucocorticoids (GC) induce apoptosis in malignant lymphoblasts, but the mechanism of this process as well as that of the clinically important GC resistance is unknown. We investigated GC resistance in Jurkat T-ALL cells in which ectopic GC receptor (GR) restores GC sensitivity, suggesting deficient GR expression. Jurkat cells expressed one wild-type and one mutated (R477H) GR allele. GR R477H ligand-bindingdependent nuclear import, as revealed by live-cell microscopy of YFP-tagged GR, was unaffected. Transactivation and transrepression were markedly impaired; however, GR R477H did not act in a dominant-negative manner, that is, did not prevent cell death, when introduced into a GC-sensitive cell line by retroviral gene transfer. Contrary to another GR heterozygous, but GC-sensitive, T-ALL model (CCRF-CEM), Jurkats expressed lower basal GR levels and did not autoinduce their GR, as revealed by 'real-time' RT-PCR and immunoblotting. Absent GR auto-induction could not be restored by transgenic GR and, hence, was not caused by reduced basal GR levels. Thus, inactivation of one GR gene results in haploinsufficiency if associated with lack of GR auto-induction.

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“…Some humans manifest a relative glucocorticoid resistance caused by GR gene mutations (Koper et al, 1997). In mice, conditional GR overexpression has been suggested as a model for increased anxiety-related behavior not secondary to altered levels of stress hormones (Muller et al, 2002).…”

Section: Hpa Axis and Crhmentioning

confidence: 99%

Discovering Endophenotypes for Major Depression

Hasler

Drevets

Manji

et al. 2004

Neuropsychopharmacol

1,022

739

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The limited success of genetic studies of major depression has raised questions concerning the definition of genetically relevant phenotypes. This paper presents strategies to improve the phenotypic definition of major depression by proposing endophenotypes at two levels: First, dissecting the depressive phenotype into key components results in narrow definitions of putative psychopathological endophenotypes: mood bias toward negative emotions, impaired reward function, impaired learning and memory, neurovegetative signs, impaired diurnal variation, impaired executive cognitive function, psychomotor change, and increased stress sensitivity. A review of the recent literature on neurobiological and genetic findings associated with these components is given. Second, the most consistent heritable biological markers of major depression are proposed as biological endophenotypes for genetic studies: REM sleep abnormalities, functional and structural brain abnormalities, dysfunctions in serotonergic, catecholaminergic, hypothalamic-pituitary-adrenocortical axis, and CRH systems, and intracellular signal transduction endophenotypes. The associations among the psychopathological and biological endophenotypes are discussed with respect to specificity, temporal stability, heritability, familiality, and clinical and biological plausibility. Finally, the case is made for the development of a new classification system in order to reduce the heterogeneity of depression representing a major impediment to elucidating the genetic and neurobiological basis of this common, severe, and often life-threatening illness.

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

Cited by 209 publications

References 26 publications

The Corticosteroid Receptor Hypothesis of Depression

The Corticosteroid Receptor Hypothesis of Depression

Glucocorticoid receptor heterozygosity combined with lack of receptor auto-induction causes glucocorticoid resistance in Jurkat acute lymphoblastic leukemia cells

Discovering Endophenotypes for Major Depression

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