Resistance to thyroid hormone (RTH) is caused by mutations of the thyroid 
hormone receptor beta (TR beta) gene. Almost all RTH patients are heterozygous 
with an autosomal dominant pattern of inheritance. That most are clinically 
euthyroid suggests a compensatory role of the TR alpha1 isoform in maintaining 
the normal functions of thyroid hormone (T3) in these patients. To understand 
the role of TR alpha1 in the manifestation of RTH, we compared the phenotypes of 
mice with a targeted dominantly negative mutant TR beta (TR betaPV) with or 
without TR alpha1. TR betaPV mice faithfully recapitulate RTH in humans in that 
these mice demonstrate abnormalities in the pituitary-thyroid axis and 
impairment in growth. Here we show that the dysregulation of the 
pituitary-thyroid axis was worsened by the lack of TR alpha1 in TR betaPV mice, 
and severe impairment of postnatal growth was manifested in TR betaPV mice 
deficient in TR alpha1. Furthermore, abnormal expression patterns of T3-target 
genes in TR betaPV mice were altered by the lack of TR alpha1. These results 
demonstrate that the lack of TR alpha1 exacerbates the manifestation of RTH in 
TR betaPV mice. Therefore, TR alpha1 could play a compensatory role in mediating 
the functions of T3 in heterozygous patients with RTH. This compensatory role 
may be especially crucial for postnatal growth.