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Resistance to thyroid hormone is modulated in vivo by the nuclear receptor corepressor (NCOR1)
Mutations in the ligand-binding domain of the thyroid hormone receptor β (TRβ) lead to resistance to thyroid hormone (RTH). These TRβ mutants function in a dominant-negative fashion to interfere with the transcription activity of wild-type thyroid hormone receptors (TRs), leading to dysregulation of...
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Published in: | Proceedings of the National Academy of Sciences - PNAS 2011-10, Vol.108 (42), p.17462-17467 |
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Main Authors: | , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Mutations in the ligand-binding domain of the thyroid hormone receptor β (TRβ) lead to resistance to thyroid hormone (RTH). These TRβ mutants function in a dominant-negative fashion to interfere with the transcription activity of wild-type thyroid hormone receptors (TRs), leading to dysregulation of the pituitary-thyroid axis and resistance in peripheral tissues. The molecular mechanism by which TRβ mutants cause RTH has been postulated to be an inability of the mutants to properly release the nuclear compressors (NCORs), thereby inhibiting thyroid hormone (TH)-mediated transcription activity. To test this hypothesis in vivo, we crossed Thrbpv mice (a model of RTH) expressing a human TRβ mutant (PV) with mice expressing a mutant Ncori alíele (Ncor1∆ID mice) that cannot recruit a TR or a PV mutant. Remarkably, in the presence of NCORI∆ID, the abnormally elevated thyroid-stimulating hormone and TH levels found in Thrbpv mice were modestly but significantly corrected. Furthermore, thyroid hyperplasia, weight loss, and other hallmarks of RTH were also partially reverted in mice expressing NCORI∆ID. Taken together, these data suggest that the aberrant recruitment of NCOR1 by RTH TRβ mutants leads to clinical RTH in humans. The present study suggests that therapies aimed at the TR-NCOR1 interaction or its downstream actions could be tested as potential targets in treating RTH. |
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ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.1107474108 |