A targeted dominant negative mutation of the thyroid hormone alpha 1 receptor causes increased mortality, infertility, and dwarfism in mice

Mutations in the thyroid hormone receptor beta (TR beta) gene result in resistance to thyroid hormone. However, it is unknown whether mutations in the TR alpha 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 TRa gene locus by means of homologous recombination (TR alpha 1PV 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 TR beta1. We knocked in the same PV mutation to the corresponding TRa gene locus to compare the phenotypes of TR alpha1(PV/+) mice with those of TR beta (PV/+) mice. TR alpha1(PV/+) mice were viable, indicating that the mutation of the TRa gene is not embryonic lethal. In drastic contrast to the TR beta (PV/+) mice, which do not exhibit a growth abnormality, TR alpha1(PV/+) mice were dwarfs. These dwarfs exhibited increased mortality and reduced fertility. In contrast to TR beta (PV/+) mice, which have a hyperactive thyroid, TR alpha1(PV/+) mice exhibited mild thyroid failure. The in vivo pattern of abnormal regulation of T3 target genes in TR alpha1(PV/+) mice was unique from those of TR beta (PV/+) mice. The distinct phenotypes exhibited by TR alpha1(PV/+) and Tr beta (PV/+) mice indicate that the in vivo functions of TR mutants are isoform-dependent. The TR alpha1(PV/+) mice may be used as a tool to uncover human diseases associated with mutations in the TR alpha gene and, furthermore, to understand the molecular mechanisms by which TR isoforms exert their biological activities.

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