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  • The EMBO Journal (2002) 21, 5079 - 5087
  • doi:10.1093/emboj/cdf523

Retardation of post-natal development caused by a negatively acting thyroid hormone receptor alpha1

Alexander Tinnikov1,7, Kristina Nordström1,7, Peter Thorén2, Jenny M. Kindblom3, Stephen Malin4, Björn Rozell5, Maria Adams6, Odelia Rajanayagam6, Sven Pettersson4, Claes Ohlsson3, Krishna Chatterjee6 and Björn Vennström1

  1. Department of Cell and Molecular Biology, Karolinska Institute, S-177 71 Stockholm, Sweden
  2. Department of Physiology and Pharmacology, Karolinska Institute, S-177 71 Stockholm, Sweden
  3. Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg University, Göteborg, Sweden
  4. Microbiology and Tumour Biology Center, Karolinska Institute, S-177 71 Stockholm, Sweden
  5. Clinical Research Center and Department of Microbiology, Pathology and Immunology, Division of Pathology, Karolinska Institutet, Huddinge University Hospital, Sweden
  6. Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK
  7. A.Tinnikov and K.Nordström contributed equally to this work

Correspondence to:

Björn Vennström, E-mail: Bjorn.Vennstrom@cmb.ki.se

Received 9 July 2002; Accepted 14 August 2002; Revised 12 August 2002

Most patients with the syndrome resistance to thyroid hormone (RTH) express a mutant thyroid hormone receptor beta (TRbeta) with transdominant negative transcriptional effects. Since no patient with a mutant TRalpha has been identified, we introduced a point mutation into the mouse thyroid hormone receptor (TRalpha1) locus originally found in the TRbeta gene, that reduces ligand binding 10-fold. Heterozygous 2- to 3-week- old mice exhibit a severe retardation of post-natal development and growth, but only a minor reduction in serum thyroxine levels. Homozygous mice died before 3 weeks of age. Adult heterozygotes overcome most of these defects except for cardiac function abnormalities, suggesting that other factors compensate for the receptor defect. However, the additional deletion of the TRbeta gene in this mouse strain caused a 10-fold increase in serum thyroxine, restored hormonal regulation of target genes for TRs, and rescued the growth retardation. The data demonstrate a novel array of effects mediated by a dominant negative TRalpha1, and may provide important clues for identification of a potentially unrecognized human disorder and its treatment.

  • Keywords:

    • thyroid hormone receptor,
    • transgenic mice