文章基本信息

标题：A targeted dominant negative mutation of the thyroid hormone α1 receptor causes increased mortality, infertility, and dwarfism in mice
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作者：Masahiro Kaneshige ; Hideyo Suzuki ; Kumiko Kaneshige 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2001
卷号：98
期号：26
页码：15095-15100
DOI：10.1073/pnas.261565798
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 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 TR gene locus by means of homologous recombination (TR1PV 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{beta}1. We knocked in the same PV mutation to the corresponding TR gene locus to compare the phenotypes of TR1PV/+ mice with those of TR{beta}PV/+ mice. TR1PV/+ mice were viable, indicating that the mutation of the TR gene is not embryonic lethal. In drastic contrast to the TR{beta}PV/+ mice, which do not exhibit a growth abnormality, TR1PV/+ mice were dwarfs. These dwarfs exhibited increased mortality and reduced fertility. In contrast to TR{beta}PV/+ mice, which have a hyperactive thyroid, TR1PV/+ mice exhibited mild thyroid failure. The in vivo pattern of abnormal regulation of T3 target genes in TR1PV/+ mice was unique from those of TR{beta}PV/+ mice. The distinct phenotypes exhibited by TR1PV/+ and TR{beta}PV/+ mice indicate that the in vivo functions of TR mutants are isoform-dependent. The TR1PV/+ mice may be used as a tool to uncover human diseases associated with mutations in the TR gene and, furthermore, to understand the molecular mechanisms by which TR isoforms exert their biological activities.