Thyroid hormone governs a diverse repertoire of physiological functions through 
receptors encoded in the receptor genes alpha and beta, which each generate 
variant proteins. In mammals, the alpha gene generates, in addition to the 
normal receptor TRalpha1, a non-hormone-binding variant TRalpha2 whose exact 
function is unclear. Here, we present the phenotype associated with the targeted 
ablation of TRalpha2 expression. Selective ablation of TRalpha2 resulted in an 
inevitable, concomitant overexpression of TRalpha1. Both TRalpha2 +/- and -/- 
mice show a complex phenotype with low levels of free T3 and free T4, and have 
inappropriately normal levels of TSH. The thyroid glands exhibit mild 
morphological signs of dysfunction and respond poorly to TSH, suggesting that 
the genetic changes affect the ability of the gland to release thyroid hormones. 
However, the phenotype of the mutant mice also has features of hyperthyroidism, 
including decreased body weight, elevated heart rate, and a raised body 
temperature. Furthermore, TRalpha2-/- and TRalpha2+/- mice are obese and exhibit 
skeletal alterations, associated with a late-onset growth retardation. The 
results thus suggest that the overexpression of TRalpha1 and the concomitant 
decrease in TRalpha2 expression lead to a mixed hyper- and hypothyroid 
phenotype, dependent on the tissue studied. The phenotypes suggest that the 
balance of TRalpha1:TRalpha2 expressed from the TRalpha gene provides an 
additional level of tuning the control of growth and homeostasis in mammalian 
species.