Glucocorticoid and mineralocorticoid resistance/hypersensitivity syndromes

in Journal of Endocrinology
Authors:
T Kino
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GP Chrousos
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DOI:
https://doi.org/10.1677/joe.0.1690437
Volume/Issue:
Volume 169: Issue 3
Article Type:
Other
Page Range:
437–445
Online Publication Date:
01 Jun 2001
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Glucocorticoids and mineralocorticoids regulate diverse functions important to maintain central nervous system, cardiovascular, metabolic, and immune homeostasis. The actions of these hormones are mediated by their specific intracellular receptors: the glucocorticoid (GR) and mineralocorticoid (MR) receptors. Pathologic conditions associated with changes of tissue sensitivity to these hormones have been described. The syndrome of familial glucocorticoid resistance is characterized by hypercortisolism without Cushing's syndrome stigmata. The molecular defects of four kindreds and one sporadic case have been elucidated as inactivating mutations in the ligand-binding domain of GR. Two cases developed glucocorticoid resistance at the heterozygous state. In these patients, mutant receptors possessed transdominant negative activity upon the wild type receptor. Insensitivity to mineralocorticoids (which may also be caused by loss of function mutations of the MR gene) was found in one sporadic case and four autosomal dominant cases of Pseudohypoaldosteronism type 1. These included two frameshift mutations and a premature termination codon in exon 2, leading to gene products lacking the entire DNA- and ligand-binding domains, and a single base-pair deletion in the intron-5 splice donor site. Tissue hypersensitivity to glucocorticoids was recently hypothesized in patients with Human Immunodeficiency Virus (HIV) type-1 infection via the accessory proteins Vpr and Tat which enhance GR transactivation. Since HIV-1 long terminal repeat (LTR) and glucocorticoid-responsive promoters use the same set of coactivators, these proteins may stimulate HIV-1-LTR and glucocorticoid-inducible genes concurrently. The former may directly stimulate viral proliferation, while the latter may indirectly enhance viral propagation by suppressing the host immune system through glucocorticoid-mediated mechanisms.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Page(s):
9
Article Type:
Other
Print Publication Date:
01 Jun 2001
Online Publication Date:
01 Jun 2001