Dataset Information

A novel point mutation in helix 10 of the human glucocorticoid receptor causes generalized glucocorticoid resistance by disrupting the structure of the ligand-binding domain.

ABSTRACT:

Context

Generalized glucocorticoid resistance syndrome is a rare familial or sporadic condition characterized by partial insensitivity to glucocorticoids, caused by mutations in the glucocorticoid receptor (GR) gene. Most of the reported cases are adults, demonstrating symptoms associated with mineralocorticoid and/or adrenal androgen excess caused by compensatively increased secretion of the adrenocorticotropic hormone.

Patient

We identified a new 2-yr-old female case of generalized glucocorticoid resistance syndrome. The patient (TJ) presented with a generalized seizure associated with hypoglycemia and hypokalemia. She also had hypertension and premature pubarche, whereas dexamethasone effectively suppressed these clinical manifestations.

Results

The patient's GR gene had a heterozygotic mutation (G-->A) at nucleotide position 2141 (exon 8), which resulted in substitution of arginine by glutamine at amino acid position 714 in the ligand-binding domain (LBD) of the GR alpha. Molecular analysis revealed that the mutant receptor had significantly impaired transactivation activity with a 2-fold reduction in affinity to ligand. It showed attenuated transactivation of the activation function (AF)-2 and reduced binding to a p160 nuclear receptor coactivator. Computer-based structural analysis revealed that replacement of arginine by glutamine at position 714 transmitted a conformational change to the LBD and the AF-2 transactivation surface, resulting in a decreased binding affinity to ligand and to the LXXLL coactivator motif.

Conclusions

Dexamethasone treatment is effective in controlling the premature pubarche, hypoglycemia, hypertension, and hypokalemia in this child case, wherein arginine 714 plays a key role in the proper formation of the ligand-binding pocket and the AF-2 surface of the GR alpha LBD.

SUBMITTER: Nader N

PROVIDER: S-EPMC2869551 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Publications

A novel point mutation in helix 10 of the human glucocorticoid receptor causes generalized glucocorticoid resistance by disrupting the structure of the ligand-binding domain.

Nader Nancy N Bachrach Bert E BE Hurt Darrell E DE Gajula Sonia S Pittman Amy A Lescher Rachel R Kino Tomoshige T

The Journal of clinical endocrinology and metabolism 20100324 5

<h4>Context</h4>Generalized glucocorticoid resistance syndrome is a rare familial or sporadic condition characterized by partial insensitivity to glucocorticoids, caused by mutations in the glucocorticoid receptor (GR) gene. Most of the reported cases are adults, demonstrating symptoms associated with mineralocorticoid and/or adrenal androgen excess caused by compensatively increased secretion of the adrenocorticotropic hormone.<h4>Patient</h4>We identified a new 2-yr-old female case of generali ...[more]

PMID: 20335448

Similar Datasets

Project description: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?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?V575G displayed significantly enhanced (?80%) ability to transrepress the nuclear factor-?? signaling pathway. Finally, the mutant receptor hGR?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?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.

Dataset Information

A novel point mutation in helix 10 of the human glucocorticoid receptor causes generalized glucocorticoid resistance by disrupting the structure of the ligand-binding domain.

Context

Patient

Results

Conclusions

Publications

A novel point mutation in helix 10 of the human glucocorticoid receptor causes generalized glucocorticoid resistance by disrupting the structure of the ligand-binding domain.

Similar Datasets

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