Mice with a targeted mutation in the thyroid hormone β receptor gene exhibit impaired growth and resistance to thyroid hormone

Patients with mutations in the thyroid hormone receptor beta (TR beta) gene manifest resistance to thyroid hormone (RTH), resulting in a constellation of variable phenotypic abnormalities. To understand the molecular basis underlying the action of mutant TR beta in vivo, we generated mice with a targeted mutation in the TR beta gene (TR beta PV; PV, mutant thyroid hormone receptor kindred PV) by using homologous recombination and the Cre/loxP system. Mice expressing a single PV allele showed the typical abnormalities of thyroid function found in heterozygous humans with RTH, Homozygous PV mice exhibit severe dysfunction of the pituitary-thyroid axis, impaired weight gains, and abnormal bone development. This phenotype is distinct from that seen in mice with a null mutation in the TR beta gene. Importantly, we identified abnormal expression patterns of several genes in tissues of TR beta PV mice, demonstrating the interference of the mutant TR with the gene regulatory functions of the wild-type Tn in vivo. These results show that the actions of mutant and wild-type TR beta in vivo are distinct. This model allows further study of the molecular action of mutant TR in vivo, which could lead to better treatment for RTH patients.