A Novel TRβ Mutation (R383H) in Resistance to Thyroid Hormone Syndrome Predominantly Impairs Corepressor Release and Negative Transcriptional Regulation

Resistance to thyroid hormone (RTH) is characterized by elevated serum thyroid hormones, failure to suppress pituitary TSH secretion, and variable T3 responsiveness in peripheral tissues. The disorder is associated with diverse mutations that cluster within three areas of the thyroid hormone β (TRβ)...

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Veröffentlicht in:Molecular endocrinology (Baltimore, Md.) Md.), 1998-05, Vol.12 (5), p.609-621
Hauptverfasser: Clifton-Bligh, R. J, de Zegher, F, Wagner, R. L, Collingwood, T. N, Francois, I, Van Helvoirt, M, Fletterick, R. J, Chatterjee, V. K. K
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Sprache:eng
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Zusammenfassung:Resistance to thyroid hormone (RTH) is characterized by elevated serum thyroid hormones, failure to suppress pituitary TSH secretion, and variable T3 responsiveness in peripheral tissues. The disorder is associated with diverse mutations that cluster within three areas of the thyroid hormone β (TRβ) receptor. Here, we report a novel RTH mutation (R383H), which is located in a region not known to harbor naturally occurring mutations. Although the R383H mutant receptor activated positively regulated genes to an extent comparable to wild-type (WT), negative transcriptional regulation of human TSHα and TRH promoters was impaired in either TRβ1 or TRβ2 contexts, and WT receptor function was dominantly inhibited. T3-dependent changes in basal transcription with R383H were also impaired: on the TRH promoter, basal activation by unliganded R383H was not reversed by T3 to the same extent as WT; similarly transcriptional silencing by an unliganded Gal4-R383H fusion was not relieved at a T3 concentration that derepressed WT. In keeping with this, ligand-dependent corepressor release by R383H, either in a protein-protein interaction assay or as a DNA-bound heterodimer with retinoid X receptor on either positive or negative thyroid hormone response elements, was disproportionately impaired relative to its ligand-binding affinity, whereas its T3-dependent recruitment of coactivator was unimpaired. These properties were shared by another previously described RTH mutant (R429Q), and in the crystal structure of TRα the homologous residues interact in a polar invagination. Our data indicate a role for these residues in mediating negative transcriptional regulation and facilitating corepressor release and suggest that predominant impairment of these functions may be the minimal requirements for causation of RTH.
ISSN:0888-8809
1944-9917
DOI:10.1210/mend.12.5.0113