Generation and Characterization of a New Resistance to Thyroid Hormone Mouse Model with Thyroid Hormone Receptor Alpha Gene Mutation
Generation and Characterization of a New Resistance to Thyroid Hormone Mouse Model with Thyroid Hormone Receptor Alpha Gene Mutation
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DOI：
10.1089/thy.2019.0733
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发表时间：
2020-10-23
期刊：
影响因子：
6.6
通讯作者：
Teng, Weiping
中科院分区：
文献类型：
--
作者：
Liang, Yue;Zhao, Defa;Teng, Weiping
Background: In humans, resistance to thyroid hormone (RTH) caused by mutations in the thyroid hormone receptor alpha (THRA) gene, RTH alpha, manifests as tissue-specific hypothyroidism and circulating thyroid hormone levels exhibit hypothyroid-like clinical features. Before the identification of patients with RTH alpha, several Thr alpha 1 knock-in mouse models were generated to clarify the function of TR alpha 1. However, the phenotypes of these mice were not consistent with the clinical presentation of RTH alpha in humans. For the present study, we generated an RTH alpha mouse model that carries the Thra1(E403X) mutation found in human RTH alpha patients. Here, we report the gross phenotypes of this mouse RTH alpha model.Methods: Traditional homologous recombination gene targeting techniques were used to introduce a mutation (Thra1(E403X)) in the mouse Thra gene. The phenotypes of the resulting mice were studied and compared with clinical features observed for RTH alpha with THRA(E403X).Results: Thr alpha 1(E403X/E403X) homozygous mice exhibited severe neurological phenotypes, such as spasticity and motor ataxia, which were similar to those observed in endemic cretinism. Thr alpha 1(E403X/+) heterozygous mice reproduced most clinical manifestations of patient with RTH alpha, such as a normal survival rate and male fertility, as well as delayed postnatal growth and development, neurological and motor coordination deficits, and anemia. The mice had typical thyroid function with a modest increase in serum triiodothyronine (T3) levels, a low thyroxine (T4)/T3 ratio, and low reverse T3 (rT3) levels.Conclusions: The Thr alpha 1(E403X/+) mice faithfully recapitulate the clinical features of human RTH alpha and thus can provide a useful tool to dissect the role of TR alpha 1 in development and to determine the pathological mechanisms of RTH alpha.
