A targeted dominant negative mutation of the thyroid hormone α1 receptor causes increased mortality, infertility, and dwarfism in mice

Mutations in the thyroid hormone receptor β (TRβ) gene result in resistance to thyroid hormone. However, it is unknown whether mutations in the TRα gene could lead to a similar disease. To address this question, we prepared mutant mice by targeting mutant thyroid hormone receptor kindred PV (PV) mutation to the TRα gene locus by means of homologous recombination (TRα1PV mice). The PV mutation was derived from a patient with severe resistance to thyroid hormone that has a frameshift of the C-terminal 14 aa of TRβ1. We knocked in the same PV mutation to the corresponding TRα gene locus to compare the phenotypes of TRα1(PV/+) mice with those of TRβ(PV/+) mice. TRα1(PV/+) mice were viable, indicating that the mutation of the TRα gene is not embryonic lethal. In drastic contrast to the TRβ(PV/+) mice, which do not exhibit a growth abnormality, TRα1(PV/+) mice were dwarfs. These dwarfs exhibited increased mortality and reduced fertility. In contrast to TRβ(PV/+) mice, which have a hyperactive thyroid, TRα1(PV/+) mice exhibited mild thyroid failure. The in vivo pattern of abnormal regulation of T3 target genes in TRα1(PV/+) mice was unique from those of TRβ(PV/+) mice. The distinct phenotypes exhibited by TRα1(PV/+) and TRβ(PV/+) mice indicate that the in vivo functions of TR mutants are isoform-dependent. The TRα1(PV/+) mice may be used as a tool to uncover human diseases associated with mutations in the TRα gene and, furthermore, to understand the molecular mechanisms by which TR isoforms exert their biological activities.