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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 98; no. 26; pp. 15095 - 15100
• Main Authors: Kaneshige, M, Suzuki, H, Kaneshige, K, Cheng, J, Wimbrow, H, Barlow, C, Willingham, M C, Cheng, S
• Format: Journal Article
• Language: English
• Published: United States 18.12.2001
• Subjects: Animals; Base Sequence; DNA Primers; Dwarfism - genetics; Gene Expression; Genes, Dominant; Infertility - genetics; Mice; Mortality; Mutation; Receptors, Thyroid Hormone - genetics; Receptors, Thyroid Hormone - physiology; Survival Analysis; Thyroid Diseases - genetics; thyroid hormone receptor ^a; thyroid hormone resistance; TR^b gene; Transcriptional Activation
• ISSN: 0027-8424
• DOI: 10.1073/pnas.261565798

Mutations in the thyroid hormone receptor beta (TRbeta) gene result in resistance to thyroid hormone. However, it is unknown whether mutations in the TRalpha 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 TRalpha gene locus by means of homologous recombination (TRalpha1PV 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 TRbeta1. We knocked in the same PV mutation to the corresponding TRalpha gene locus to compare the phenotypes of TRalpha1(PV/+) mice with those of TRbeta(PV/+) mice. TRalpha1(PV/+) mice were viable, indicating that the mutation of the TRalpha gene is not embryonic lethal. In drastic contrast to the TRbeta(PV/+) mice, which do not exhibit a growth abnormality, TRalpha1(PV/+) mice were dwarfs. These dwarfs exhibited increased mortality and reduced fertility. In contrast to TRbeta(PV/+) mice, which have a hyperactive thyroid, TRalpha1(PV/+) mice exhibited mild thyroid failure. The in vivo pattern of abnormal regulation of T3 target genes in TRalpha1(PV/+) mice was unique from those of TRbeta(PV/+) mice. The distinct phenotypes exhibited by TRalpha1(PV/+) and TRbeta(PV/+) mice indicate that the in vivo functions of TR mutants are isoform-dependent. The TRalpha1(PV/+) mice may be used as a tool to uncover human diseases associated with mutations in the TRalpha gene and, furthermore, to understand the molecular mechanisms by which TR isoforms exert their biological activities.