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.