A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo

Danielle S. Machado, Amin Sabet, Leticia A. Santiago, Aniket R. Sidhaye, Maria I. Chiamolera, Tania M. Ortiga-Carvalho, Fredric E. Wondisford

Research output: Contribution to journalArticlepeer-review

Abstract

Resistance to thyroid hormone (RTH) is most often due to point mutations in the β-isoform of the thyroid hormone (TH) receptor (TR-β). The majority of mutations involve the ligand-binding domain, where they block TH binding and receptor function on both stimulatory and inhibitory TH response elements. In contrast, a few mutations in the ligand-binding domain are reported to maintain TH binding and yet cause RTH in certain tissues. We introduced one such naturally occurring human RTH mutation (R429Q) into the germline of mice at the TR-β locus. R429Q knock-in (KI) mice demonstrated elevated serum TH and inappropriately normal thyroid-stimulating hormone (TSH) levels, consistent with hypothalamic-pituitary RTH. In contrast, 3 hepatic genes positively regulated by TH (Dio1, Gpd1, and Thrsp) were increased in R429Q KI animals. Mice were then rendered hypothyroid, followed by graded T3 replacement. Hypothyroid R429Q KI mice displayed elevated TSH subunit mRNA levels, and T 3 treatment failed to normally suppress these levels. T3 treatment, however, stimulated pituitary Gh levels to a greater degree in R429Q KI than in control mice. Gsta, a hepatic gene negatively regulated by TH, was not suppressed in R429Q KI mice after T3 treatment, but hepatic Dio1 and Thrsp mRNA levels increased in response to TH. Cardiac myosin heavy chain isoform gene expression also showed a specific defect in TH inhibition. In summary, the R429Q mutation is associated with selective impairment of TH-mediated gene repression, suggesting that the affected domain, necessary for TR homodimerization and corepressor binding, has a critical role in negative gene regulation by TH.

Original languageEnglish (US)
Pages (from-to)9441-9446
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number23
DOIs
StatePublished - Jun 9 2009

Keywords

  • Corepressor
  • Homodimer
  • Negative regulation
  • Resistance to thyroid hormone

ASJC Scopus subject areas

  • General

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