The TR genes and mutationsThe TRα a

The TR genes and mutationsThe TRα and TRβ genes, located on chromosomes 17 and 3, respectively, encode proteins of structural and sequence similarities. Both genes produce two isoforms; α1 and α2 by alternative splicing, and β1 and β2 by different transcription start points. TRα2 binds to TREs but, as the result of a sequence difference at the ligand-binding domain site, it does not bind TH and thus does not function as a proper TR.25 Moreover, it appears to have a weak antagonistic effect.26 Additional TR isoforms, including a TRβ with shorter amino terminus (TRβ3) and truncated molecules (ΔTRβ3, ΔTRα1 and ΔTRα2) lacking the DNA-binding domain, have been identified in different tissues of rodents.27, 28 The last three exhibit a dominant antagonistic effect but their significance in humans remains unknown.29The relative expression and product distribution of the two TR genes vary among tissues and during different stages of development. To a certain degree, TRβ and TRα are interchangeable.30, 31 However, the compensatory effects observed in the absence of one of the receptors are not complete and some TH effects are TR isoform specific (see the section Animal models, below).