Characterization of two novel mutations in the glucocorticoid receptor gene in patients with primary cortisol resistance

Ruiz, Mini; Lind, Ulrika; Gåfvels, Mats; Eggertsen, Gösta; Carlstedt‐Duke, Jan; Nilsson, Lennart; Holtmann, Martin; Stierna, Pontus; Wikström, Ann–Charlotte; Werner, Sigbritt

doi:10.1046/j.1365-2265.2001.01323.x

Cited by 146 publications

(117 citation statements)

References 29 publications

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“…In agreement with the above-mentioned reports, 26,27 transfection of GR wt resulted in dose-dependent induction of Figure 1 The GR gene of Jurkat cells contains a point mutation in codon 477. Jurkat GR cDNA was PCR-amplified, subcloned into an expression vector and sequenced.…”

Section: Resultssupporting

confidence: 90%

“…GR R477H mutation impairs transactivation and transrepression, but not ligand binding or translocation, and is not dominant negative Interestingly, the GR R477H mutation was previously observed in a patient with primary cortisol resistance (in combination with a GR wt allele) 26 and in a GC-resistant subclone of the mouse S49 thymoma line (where R477 corresponds to R484), in association with the mouse GR E546G mutation on the second allele. 27 The mutation did not detectably affect ligand binding in either system nor change the GR affinity (tested in the human system only).…”

Section: Resultsmentioning

confidence: 90%

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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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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 90%

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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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Raef¹,

Baitei²,

Zou³

et al. 2008

European Journal of Endocrinology

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Objective: Glucocorticoid resistance is a rare sporadic or familial condition that is characterized by generalized, partial resistance to glucocorticoids. It is caused by a mutation in the glucocorticoid receptor-a (GR-a) gene. We aimed to understand the reasons for different phenotypes (severe to asymptomatic) observed in a family with primary cortisol resistance. Design: The genotype leading to cortisol resistance in the family members was investigated and correlated to the clinical phenotype. Method: Three siblings were presented with clinical cortisol resistance, featuring severe hypertension, hypokalemia and hyperandrogenism. Three other siblings and both parents were asymptomatic. Genomic DNA from peripheral lymphocytes was isolated from family members. The entire GR-a coding sequence (exons 2-9) was amplified by PCR and sequenced. Results: A homozygous G679S mutation was present in the three clinically affected subjects. Heterozygous G66A (E22E) and G68A (R23K) polymorphisms and G2035A (G679S) mutation were found in the father and two siblings. Mother and one sibling had only heterozygous G679S mutation. The clinically unaffected subjects showed two different responses to dexamethason. Those with heterozygous G679S mutation and ER22/23EK polymorphism had normal cortisol suppression, whereas those with only heterozygous G679S mutation failed to suppress normally. Conclusions: A homozygous G679S mutation of the GR-a gene is associated with severe cortisol resistance, whereas a heterozygous mutation of the same gene can lead to subclinical cortisol resistance. The effect of the heterozygous mutation was abolished in subjects carrying the ER22/23EK polymorphism.

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“…1A and B; refs. [6][7][8][9][10]. Besides somatic mutations, polymorphisms within the GR gene have been described in healthy populations ( Table 1), of which some were associated with altered responsiveness to glucocorticoid.…”

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Genetic Variations in the Glucocorticoid Receptor Gene Are Not Related to Glucocorticoid Resistance in Childhood Acute Lymphoblastic Leukemia

Tissing

Meijerink

Boer

et al. 2005

Clinical Cancer Research

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Glucocorticoid sensitivity is an important prognostic factor in pediatric acute lymphoblastic leukemia (ALL). For its antileukemic effect, glucocorticoid binds the intracellular glucocorticoid receptor (GR) subsequently regulating transcription of downstream genes.We analyzed whether genetic variations within the GR gene are related to differences in the cellular response to glucocorticoids. Methods: In leukemic samples of 57 children, the GR gene was screened for nucleotide variations using a PCR/single-strand conformational polymorphism sequencing strategy. Data were linked to in vivo and in vitro glucocorticoid resistance. Results: No somatic mutations were detected in the GR gene coding region, but six polymorphisms (i.e., ER22/23EK, N363S, BclI, intron mutation 16 bp upstream of exon 5, H588H, and N766N) were identified. In 67% of ALL cases, at least one minor allele of these polymorphisms was detected. Although only borderline significant, the incidence for the N363S polymorphism minor allele was higher (12% versus 6%, P = 0.06) and for the ER22/23EK minor allele lower (4% versus 7.6%, P = 0.1) than in a healthy, comparable population. The different genotypes of the polymorphisms were not related to prednisone resistance. In conclusion, polymorphisms but not somatic mutations in the GR gene coding region occur in leukemic blasts of children with ALL. Our data suggest that these genetic variations are not a major contributor for differences in cellular response to glucocorticoids in childhood ALL. The higher incidence of the N363S minor allele and the lower incidence of the ER22/23EK minor allele in our ALL population as compared with a normal population warrants further research.

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Characterization of two novel mutations in the glucocorticoid receptor gene in patients with primary cortisol resistance

Cited by 146 publications

References 29 publications

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

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

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

Genetic Variations in the Glucocorticoid Receptor Gene Are Not Related to Glucocorticoid Resistance in Childhood Acute Lymphoblastic Leukemia

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