Two Polymorphisms in the Glucocorticoid Receptor Gene Directly Affect Glucocorticoid-Regulated Gene Expression

Russcher, Henk; Smit, Pauline; Akker, Erica L T van den; Rossum, Elisabeth F.C. van; Brinkmann, Albert O.; Jong, Frank H. de; Lamberts, Steven W. J.; Koper, Jan W.

doi:10.1210/jc.2005-0646

Cited by 175 publications

(131 citation statements)

References 36 publications

Supporting

Mentioning

115

Contrasting

Unclassified

Order By: Relevance

“…N363S and R23K lie within the transactivation domain encoded by exon 2, and in vitro experiments revealed differences in their transactivating capacities as compared with the wildtype protein (19). For N363S, marked changes in gene expression were detected by microarray studies even without ligand incubation (20).…”

Section: Discussionmentioning

confidence: 99%

Functional glucocorticoid receptor gene variants do not underlie the high variability of 17-hydroxyprogesterone screening values in healthy newborns

Schreiner

Tozakidou²,

Maslak³

et al. 2009

European Journal of Endocrinology

View full text Add to dashboard Cite

Objective: 17-Hydroxyprogesterone (17-OHP) screening for classical congenital adrenal hyperplasia (CAH) is part of many newborn screening programs worldwide. Cut-off values are relatively high, and screening sensitivity does not reach 100%. Recently, the glucocorticoid receptor (GR) N363S-variant has been linked to relatively low degree of virilization and comparatively lower 17-OHP serum concentrations in clinically diagnosed female CAH patients. We sought to determine whether functional GR gene variants, either increasing (N363S, BclI) or decreasing GR sensitivity (R23K), underlie the variable 17-OHP screening levels in healthy newborns. Design: GR genotypes were compared with 17-OHP screening values in 1000 random samples from routine screening. 17-OHP was measured by conventional immunoassay (TRFIA) and a liquid chromatography-tandem mass spectrometry method (LC-MS/MS), which has been shown to increase screening specificity by steroid profiling and avoiding cross-reactions of the 17-OHP-antibody. Results: There was no significant association of 17-OHP with GR genotypes, even after inclusion of gestational and postnatal age as covariates. However, among LC-MS/MS steroid measurements, we observed some unexpected trends, including lower 11-deoxycortisol concentrations in both 363S-and 23K-carriers. For carriers of the frequent BclI variant, linear regression analysis revealed a significant increase of 4-androstenedione levels with every mutant allele inherited. Conclusions: Functional GR variants do not underlie the variation of 17-OHP values observed in healthy individuals. However, whether and to which extent genetically determined differences in individual GR sensitivity influence 17-OHP screening levels in conditions of a pathological hypothalamus-pituitary-adrenal gland-axis stimulation and thus may explain false-negative screening results in those affected by CAH remains to be investigated.

show abstract

Section: Discussionmentioning

confidence: 99%

Functional glucocorticoid receptor gene variants do not underlie the high variability of 17-hydroxyprogesterone screening values in healthy newborns

Schreiner

Tozakidou²,

Maslak³

et al. 2009

European Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…In vitro, the N363S polymorphism has been shown to be associated with increased glucocorticoid sensitivity, resulting in an increased transactivating capacity, while having no influence on the repressing capacity of the GR in COS-1 cells (24). Also, a greater sensitivity to DEX in the carriers' lymphocytes in mitogen-induced cell proliferation assay has been reported.…”

Section: Discussionmentioning

confidence: 99%

Potential advantage of N363S glucocorticoid receptor polymorphism in 21-hydroxylase deficiency

Luczay¹,

Török²,

Ferenczi³

et al. 2006

eur j endocrinol

View full text Add to dashboard Cite

Objective: Congenital adrenal hyperplasia (CAH) shows a range of severity which is explained in part by the different mutations of the CYP21 gene. To better understand the incomplete concordance between genotype and phenotype in CAH the role of the sensitizing N363S polymorphism of the glucocorticoid receptor (GR) was examined in CAH patients. Design: CAH patients were screened for N363S. Laboratory findings and clinical characteristics of carriers and non-carriers were analyzed retrospectively. Methods: The CYP21 gene of 200 CAH patients was analyzed by allele-specific PCR. The GR gene was tested for N363S by PCR followed by restriction fragment length polymorphism. Antropometric data (height, weight), degree of intrauterine virilization, hormone concentrations (17-OH-progesterone, dehydroepiandrosterone (DHEA), aldosterone, testosterone, plasma renin activity), substitution doses and clinical course were analyzed. Results: The carrier frequency of N363S in CAH patients was equivalent to that of the general Hungarian population (6% vs 7.8%). Interestingly, none of the non-classical CAH (NC-CAH) patients were carriers of the polymorphism. Carrier girls had milder genital virilization than mutation-matched non-carrier controls. There was no significant difference between the carriers and non-carriers in either the substitution doses, the hormonal, or the auxiological parameters. Conclusions: The association of sensitizing the GR variant with impaired cortisol production in CAH might be compensatory in mild NC-CAH and may prevent severe intrauterine virilization in classical form. Although the exact role of N363S in extrauterine life should be further investigated, the consideration of certain genetic polymorphisms of CAH patients may lead to better, individualized therapeutic regimes.European Journal of Endocrinology 154 859-864

show abstract

“…[45,54,[57][58][59] It should also be recognized that the effects of either state are likely to differ, depending on the target tissue involved and that ''relative'' conditions of either hyper-or hypocortisolism may exist at the same time within organisms, making any global statements a simplification of the underlying endocrine state. [60][61][62][63] For example, different GR polymorphisms can significantly affect individuals' responses to GCs, [35,64] and alternative splicing of the GR mRNA can lead to different GR isoforms with different actions in different tissues. [65,66] Furthermore, early life events, such as childhood abuse, can epigenetically reprogram GR expression and splicing, leading to important interindividual differences in GC responsivity.…”

Section: Glucocorticoids and Neurosteroidsmentioning

confidence: 99%

Depression gets old fast: do stress and depression accelerate cell aging?

et al. 2010

View full text Add to dashboard Cite

Two Polymorphisms in the Glucocorticoid Receptor Gene Directly Affect Glucocorticoid-Regulated Gene Expression

Abstract: The presence of these and other GC sensitivity-modulating polymorphisms may have consequences for the use of GCs in a clinical setting.

Cited by 175 publications

References 36 publications

Functional glucocorticoid receptor gene variants do not underlie the high variability of 17-hydroxyprogesterone screening values in healthy newborns

Functional glucocorticoid receptor gene variants do not underlie the high variability of 17-hydroxyprogesterone screening values in healthy newborns

Potential advantage of N363S glucocorticoid receptor polymorphism in 21-hydroxylase deficiency

Depression gets old fast: do stress and depression accelerate cell aging?

Contact Info

Product

Resources

About