TY - JOUR
T1 - Syndromes of thyroid hormone resistance due to mutations in the T3̄ receptor
T2 - Progress in our understanding
AU - Beck-Peccoz, P.
AU - Mannavola, D.
AU - Persani, L.
PY - 2000
Y1 - 2000
N2 - 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 thyroid-stimulating hormone (TSH) concentrations. About 85% of patients with RTH harbor mutations in thyroid hormone receptor β (TRβ). These mutations cluster in three different 'hot spots' in the ligand (T3) binding domain of the receptor. When mapped to their homologous residues in the thyroid hormone receptor (TR) crystal structure, these three clusters of mutations border the T3-binding pocket. As a consequence, most TRβ mutations impair the hormone binding to the receptor and interfere with the mechanisms of corepressor release and 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 is severely disrupted. The lack of interaction with coactivators appears to be an additional mechanism for the dominant negative effects of mutant TRβ on the transcriptional activity of the normal (wild-type) TRs. (C) 2000 Lippincott Williams and Wilkins, Inc.
AB - 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 thyroid-stimulating hormone (TSH) concentrations. About 85% of patients with RTH harbor mutations in thyroid hormone receptor β (TRβ). These mutations cluster in three different 'hot spots' in the ligand (T3) binding domain of the receptor. When mapped to their homologous residues in the thyroid hormone receptor (TR) crystal structure, these three clusters of mutations border the T3-binding pocket. As a consequence, most TRβ mutations impair the hormone binding to the receptor and interfere with the mechanisms of corepressor release and 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 is severely disrupted. The lack of interaction with coactivators appears to be an additional mechanism for the dominant negative effects of mutant TRβ on the transcriptional activity of the normal (wild-type) TRs. (C) 2000 Lippincott Williams and Wilkins, Inc.
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U2 - 10.1097/00060793-200010000-00013
DO - 10.1097/00060793-200010000-00013
M3 - Article
AN - SCOPUS:0033800061
VL - 7
SP - 281
EP - 287
JO - Current Opinion in Endocrinology and Diabetes
JF - Current Opinion in Endocrinology and Diabetes
SN - 1068-3097
IS - 5
ER -