Familial/sporadic glucocorticoid resistance syndrome and hypertension.
Glucocorticoids regulate diverse functions important for the maintenance of central nervous system, cardiovascular, metabolic, and immune homeostasis. The actions of these hormones are mediated by the specific intracellular glucocorticoid receptors (GRs). Pathologic conditions associated with changes of tissue sensitivity to these hormones have been described. The syndrome of familial/sporadic glucocorticoid resistance is characterized by hypercortisolism without Cushing syndrome stigmata. Many of the patients present with hypertension, with or without hypokalemic alkalosis, as a result of elevated concentrations of cortisol and other salt-retaining steroids. The molecular defects of 4 kindreds and one sporadic case have been elucidated as inactivating mutations in the ligand-binding domain of the GR. In two patients in whom the GR was mutated at amino acid isoleucine 559 to aspartic acid (GRalphaI559N) and isoleucine 747 to methionine (GRalphaI747M), respectively, glucocorticoid resistance developed at the heterozygous state, with transdominant negative activity of each of the mutant receptors upon the wild-type protein. Retention of the wild-type receptor in the cytoplasm by the mutant receptor was found in the former, while inappropriate accumulation of p160-type coactivators on the promoter region of glucocorticoid-responsive genes, because of a defective interaction between the AF2 region of the mutant receptor and the LXXLL motif of the coactivators, was determined in the latter. These results suggest that the pathologic mechanisms of glucocorticoid resistance is quite broad, and this is reflected in the wide variability of the clinical picture in patients with the syndrome.
Kino
Tomoshige
T
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development/NIH, Building 10, Room 9D42, 10 Center Drive MSC 1583, Bethesda, MD 20892, USA. kinot@mail.nih.gov
Vottero
Alessandra
A
Charmandari
Evangelia
E
Chrousos
George P
GP
D000308:Adrenocortical Hyperfunction / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D003907:Dexamethasone / Q000627:therapeutic use; D005938:Glucocorticoids / Q000378:metabolism* / Q000627:therapeutic use; D006706:Homeostasis; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D009154:Mutation; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone