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Transgenic Mice Bearing a Human Mutant Thyroid Hormone βl Receptor Manifest Thyroid Function Anomalies, Weight Reduction, and Hyperactivity

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Abstract

Background

Resistance to thyroid hormone (RTH) is a syndrome characterized by refractoriness of the pituitary and/or peripheral tissues to the action of thyroid hormone. Mutations in the thyroid hormone receptor β (TRβ) gene result in TRβl mutants that mediate the clinical phenotype by interfering with transcription of thyroid hormone-regulated genes via a dominant negative effect. In this study, we developed transgenic mice harboring PV, a potent dominant negative human mutant TRβl devoid of thyroid hormone binding and transcriptional activation, as an animal model to understand the molecular basis of this human disease.

Materials and Methods

Standard molecular biology approaches were used to obtain a cDNA fragment containing mutant PV which was injected into the pronucleus of fertilized egg. Founders were identified by Southern analysis and the expression of PV in tissues was determined by RNA and immunohistochemistry. Thyroid function was determined by radioimmunoassays of the hormones and the behavior of mice was observed using standard methods.

Results

The expression of mutant PV was directed by the β-actin promoter. Mutant PV mRNA was detected in all tissues of transgenic mice, but the levels varied with tissues and with different lines of founders. Thyroid function tests in transgenic mice with high expression of mutant PV showed a significantly (∼1.5-fold) higher mean serum total of L-thyroxine levels (p < 0.01) than those of nontransgenic mice. Moreover, thyroid-stimulating hormone levels were not significantly different from those of nontransgenic mice. In addition, these mice displayed decreased weights and a behavioral phenotype characterized by hyperactivity.

Conclusions

These mice have phenotypic features consistent with the commonly observed clinical features of RTH and could be used as a model system to better understand the action of mutant TRβl in a physiological context, which could lead to better treatment for this disease.

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Acknowledgments

We thank Yetem Eshete for expert care of the mice and assistance with various mouse rodent procedures, Michael Smith, M.D. (Department of Pathology and Laboratory Medicine, Medical University of South Carolina), for advice in the interpretation of the neuronal distribution of reactive nuclei in sections of mouse brain, Philip Skolnick, Ph.D., for helpful discussions regarding the behavioral phenotype of our mice, William Wood, Ph.D., and Virginia Sarapura, M.D., for the mouse TRβl plasmid, Fredric Wondisford, M.D., Christoph Meier, M.D., Peter Hauser, M.D., and John Matochik, Ph.D., for helpful discussions, Mark Pineda for technical assistance and Mathis Grossmann, M.D., Simeon Taylor, M.D., and Françoise Davis, M.D., for critical review of the manuscript.

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Authors and Affiliations

  1. Molecular and Cellular Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA

    Rosemary Wong, Vyacheslav V. Vasilyev, David I. Kutler & Bruce D. Weintraub

  2. Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    Yuan-Tsang Ting &  Sheue-yann Cheng

  3. Department of Pathology & Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA

    Mark C. Willingham

Authors
  1. Rosemary Wong
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  2. Vyacheslav V. Vasilyev
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  3. Yuan-Tsang Ting
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  4. David I. Kutler
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  5. Mark C. Willingham
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  6. Bruce D. Weintraub
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  7. Sheue-yann Cheng
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Correspondence to Sheue-yann Cheng.

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Communicated by I. Pastan.

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Wong, R., Vasilyev, V.V., Ting, YT. et al. Transgenic Mice Bearing a Human Mutant Thyroid Hormone βl Receptor Manifest Thyroid Function Anomalies, Weight Reduction, and Hyperactivity. Mol Med 3, 303–314 (1997). https://doi.org/10.1007/BF03401809

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  • DOI: https://doi.org/10.1007/BF03401809

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