Abnormal glucocorticoid receptor gene and mRNA in primary cortisol resistance

Linder, Morton; Thompson, E. Brad

doi:10.1016/0022-4731(89)90259-8

Cited by 16 publications

(5 citation statements)

References 25 publications

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“…The molecular basis for GC resistance in the various reported kindreds includes reduced GR numbers, decreased binding affinity for GC, or poor DNA binding of their GR to GRE. 48,49 Although most asthmatics respond to GC therapy, a subset of asthmatics have poorly controlled asthma even when treated with systemic GC. These patients have been referred to as steroid-resistant or steroid-insensitive asthmatics.…”

Section: Pharmacogenetics Of Glucocorticoids In Asthmamentioning

confidence: 99%

The pharmacogenetics of asthma: a candidate gene approach

et al. 2001

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Section: Pharmacogenetics Of Glucocorticoids In Asthmamentioning

confidence: 99%

The pharmacogenetics of asthma: a candidate gene approach

et al. 2001

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“…The primary structure of the human GR (hGR) has been deduced from complementary (c) DNA cloning (2), and the hGR gene has been localized on chromosome 5 (2,3). It has been suspected that a mutation in the hGR gene is responsible for the syndrome of familial glucocorticoid resistance (FGR) (4)(5)(6)(7). In this condition, serum cortisol concentrations and cortisol production rate are greatly increased, without the characteristic clinical and biochemical stigmata of glucocorticoid excess.…”

Section: Introductionmentioning

confidence: 99%

Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance.

Hurley¹,

Accili²,

Stratakis³

et al. 1991

J. Clin. Invest.

343

177

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Familial glucocorticoid resistance is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations in the absence of stigmata of Cushing's syndrome. Our previous studies of the first reported kindred showed a two-to threefold reduction in glucocorticoid receptorligand binding affinity in the propositus, and a lesser reduction in affinity in his mildly affected son and nephew. Glucocorticoid receptor cDNA from these three patients was amplified by polymerase chain reaction and sequenced. The cDNA nucleotide sequence was normal, except for nucleotide 2054, which substituted valine for aspartic acid at amino acid residue 641. The propositus was homozygous while the other relatives were heterozygous for the mutation. COS-7 monkey kidney cells were cotransfected with expression vectors for either wild type or Val 641-mutant receptors, together with the reporter plasmid pMMTV-CAT. Dexamethasone increased chloramphenicol acetyltransferase activity in cells expressing wild type receptor, but had no effect in cells expressing Val 641-mutant receptors, despite similar receptor concentrations, as indicated by Western blotting. The binding affinity for dexamethasone of the Val 641-mutant receptor was threefold lower than that of the wild type receptor. These results suggest that glucocorticoid resistance in this family is due to a point mutation in the steroidbinding domain of the glucocorticoid receptor. (J. Clin. Invest.

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“…Familial GC resistance has been described 11–13 . Genomic mutation in the glucocorticoid receptor (GR) gene has been reported in several cases.…”

Section: Is Steroid Resistance a Systemic Or Local Phenomenon?mentioning

confidence: 99%

Current understanding and problems of steroid-resistant asthma

Mori

2000

Allergology International

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Topical and systemic glucocorticoids have long been considered the most effective therapy for chronic asthma. Asthma patients who do not respond to systemic administration of high-dose glucocorticoids are termed 'steroid-resistant asthmatics'. Recent progress in the mechanisms of glucocorticoid action goes a long way to the understanding of steroid resistance. Several cellular responses to glucocorticoids have been characterized in steroid-resistant asthma. Based on molecular biological studies, excessive expression of glucocorticoid receptor β and c-fos, an inducible transcription factor, was suggested to result in steroid resistance. A thorough understanding of the pathophysiology of steroid-resistant asthma would facilitate the development of more powerful agents for the treatment of severe asthma.

show abstract

Abnormal glucocorticoid receptor gene and mRNA in primary cortisol resistance

Cited by 16 publications

References 25 publications

The pharmacogenetics of asthma: a candidate gene approach

The pharmacogenetics of asthma: a candidate gene approach

Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance.

Current understanding and problems of steroid-resistant asthma

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