Syndromes of thyroid hormone resistance.
Thyroid hormone resistance (RTH) is a rare autosomal dominant disorder, characterized clinically by goiter and biochemically by elevated circulating free thyroid hormone levels in the presence of measurable serum TSH concentrations. About 85% of patients with RTH are harboring mutations in thyroid hormone receptor beta (TRB). These mutations cluster in three different "hot spot" in the T3 binding domain of the receptor. When mapped to their homologous residues in the TR crystal structure, these three clusters of mutations border the T3-binding pocket. As a consequence, most TRB mutations impair the hormone binding to the receptor and interfere with the mechanism(s) of corepressor release and the consequent recruitment of coactivators. Thus, the remodeling of chromatin structure throughout the process of histone acetylation is prevented and the transcriptional activity of the mutant receptor on both positively and negatively regulated genes, severely disrupted. The lack of interaction with coactivators appears to be an additional mechanism for the dominant negative effects of mutant TRB on the transcriptional activity of the normal receptor.
Institute of Endocrine Sciences, University of Milan, Ospedale Maggiore IRCCS, Padiglione Granelli, 20122-Milano, Italy. paolo.beckpeccoz@unimi.it
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Beck-Peccoz
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Mannavola
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Persani
D019943:Amino Acid Substitution; D006801:Humans; D016297:Mutagenesis, Site-Directed; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D013577:Syndrome; D037042:Thyroid Hormone Receptors beta; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics*; D013963:Thyroid Hormones / Q000235:genetics*
D011988:Receptors, Thyroid Hormone; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones