Syndrome of resistance to thyroid hormone: insights into thyroid hormone action.

Détails

ID Serval
serval:BIB_ACA9FDF168BA
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Syndrome of resistance to thyroid hormone: insights into thyroid hormone action.
Périodique
Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine
Auteur⸱e⸱s
Kopp P., Kitajima K., Jameson J.L.
ISSN
0037-9727 (Print)
ISSN-L
0037-9727
Statut éditorial
Publié
Date de publication
01/1996
Peer-reviewed
Oui
Volume
211
Numéro
1
Pages
49-61
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't ; Review
Publication Status: ppublish
Résumé
Thyroid hormones (T3, T4) exert multiple cellular effects through nuclear thyroid hormone receptors (TR alpha, TR beta). Thyroid hormone receptors are transcription factors that act by altering patterns of gene expression. Resistance to thyroid hormone (RTH) is a rare disorder caused by mutations in the TR beta gene. Biochemically, the syndrome is defined by elevated circulating levels of free thyroid hormones due to reduced target tissue responsiveness and normal, or elevated, levels of thyroid-stimulating hormone (TSH). This "inappropriate" TSH elevation contrasts with the situation in hyperthyroidism, where the pituitary secretion of TSH is suppressed. Patients with RTH usually present with goiter and an euthyroid or mildly hypothyroid metabolic state. Thus, pituitary resistance results in hypersecretion of TSH, which compensates, at least in part, for hormone resistance in peripheral tissues. Despite this compensation, clinical effects of RTH can include short stature, delayed bone maturation, hyperactivity, learning disabilities, and hearing defects, as well as variable features of hyper- and hypothyroidism. With the exception of a single sibship, which harbored a deletion of the entire coding sequence of the TR beta gene and a recessive pattern of inheritance, all other cases of RTH have been inherited in an autosomal dominant manner or have been de novo heterozygous mutations of the TR beta gene. The dominant pattern of inheritance is explained by the functional properties of the mutant receptors which act in a dominant negative manner to block the activity of normal TR alpha and TR beta receptors. Now that a large number of different RTH mutations have been identified, it is striking that the mutations are clustered within restricted domains in the carboxyterminal region of the receptor. Mutations in these regions have been shown to preserve critical receptor functions such as dimerization and DNA binding, while inactivating other activites such as T3 binding and transcriptional activation. The examination of patients with RTH and their mutated receptors has provided important insights into the mechanisms of thyroid hormone action, the structure-function relationship of the receptors, and the molecular mechanisms of dominant negative activity.
Mots-clé
Amino Acid Sequence, Animals, Binding Sites, DNA/metabolism, Gene Expression Regulation/drug effects, Humans, Molecular Sequence Data, Receptors, Thyroid Hormone/chemistry, Receptors, Thyroid Hormone/genetics, Receptors, Thyroid Hormone/physiology, Thyroid Hormone Resistance Syndrome/etiology, Thyroid Hormone Resistance Syndrome/genetics, Thyroid Hormone Resistance Syndrome/therapy, Thyroid Hormones/pharmacology, Transcriptional Activation
Pubmed
Web of science
Création de la notice
30/12/2020 16:43
Dernière modification de la notice
31/12/2020 7:26
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