Glucocorticoid and mineralocorticoid resistance/hypersensitivity syndromes

Tomoshige Kino, G. P. Chrousos

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)437-445
Number of pages9
JournalJournal of Endocrinology
Volume169
Issue number3
DOIs
Publication statusPublished - 2001
Externally publishedYes

Fingerprint

Mineralocorticoids
Glucocorticoids
Hypersensitivity
HIV Long Terminal Repeat
HIV-1
RNA Splice Sites
Cushing Syndrome
vpr Gene Products
Pseudohypoaldosteronism
Hormones
tat Gene Products
Genes
Ligands
Christianity
Mineralocorticoid Receptors
Frameshift Mutation
Mutation
Nonsense Codon
Glucocorticoid Receptors
Virus Diseases

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Glucocorticoid and mineralocorticoid resistance/hypersensitivity syndromes. / Kino, Tomoshige; Chrousos, G. P.

In: Journal of Endocrinology, Vol. 169, No. 3, 2001, p. 437-445.

Research output: Contribution to journalArticle

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