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Marked Potentiation of the Dominant Negative Action of a Mutant Thyroid Hormone Receptor ß in Mice by the Ablation of One Wild-Type ß Allele

Laboratory of Molecular Biology (H.S., X.-Y.Z., S.-Y.C.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4264; Department of Human Genetics (D.F.), Mount Sinai School of Medicine, New York, New York 10029; and Department of Pathology (M.C.W.), Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Address all correspondence and requests for reprints to: Dr. S.-Y. Cheng, Laboratory of Molecular Biology, National Cancer Institute, 37 Convent Drive, Room 5128, Bethesda, Maryland 20892-4264. E-mail: sycheng{at}helix.nih.gov.

Mutations in the thyroid hormone receptor (TR) ß gene result in resistance to thyroid hormone (RTH), characterized by reduced sensitivity of tissues to thyroid hormone. To understand which physiological TR pathways are affected by mutant receptors, we crossed mice with a dominantly negative TRß mutation (TRßPV) with mice carrying a TRß null mutation (TRß^-/-) to determine the consequences of the TRßPV mutation in the absence of wild-type TRß. TRß^PV/- mice are distinct from TRß^+/- mice that did not show abnormalities in thyroid function tests. TRß^PV/- mice are also distinct from TRß^PV/+ and TRß^-/- mice in that the latter shows mild dysfunction in the pituitary-thyroid axis, whereas the former exhibit very severe abnormalities, including extensive papillary hyperplasia of the thyroid epithelium, indistinguishable from that observed in TRß^PV/PV mice. Similar to TRß^PV/PV mice, TRß^PV/- mice exhibited impairment in weight gain. Moreover, the abnormal regulation patterns of T₃-target genes in the tissues of TRß^PV/- and TRß^PV/PV mice were strikingly similar. Using TR isoforms and PV-specific antibodies in gel shift assays, we found that in vivo, PV competed with TR1 for binding to thyroid hormone response elements in TRß^PV/- mice as effectively as in TRß^PV/PV mice. Thus, the actions of mutant TRß are markedly potentiated by the ablation of the second TRß allele, suggesting that interference with wild-type TR1-mediated gene regulation by mutant TRß leads to severe RTH.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ

Ligands:   Thyroid hormone

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