Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.
Translational Center for Stem Cell Research, Tongji Hospital, Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai, 200065, China.
Sci Rep. 2018 Mar 5;8(1):4004. doi: 10.1038/s41598-018-22405-7.
Thyroid stimulating hormone receptor (TSHR), a G-protein-coupled receptor, is important for thyroid development and growth. In several cases, frameshift and/or nonsense mutations in TSHR were found in the patients with congenital hypothyroidism (CH), however they have not been functionally studied in an animal model. In the present work, we generated a unique Tshr rat model that recapitulates the phenotypes in TSHR Y444X patient by CRISPR/Cas genome editing technology. In this rat model, TSHR is truncated at the second transmembrane domain, leading to CH phenotypes as what was observed in the patients, including dwarf, thyroid aplasia, infertility, TSH resistant as well as low serum thyroid hormone levels. The phenotypes can be reversed, at least partially, by levothyroxine (L-T4) treatment after weaning. The thyroid development is severely impaired in the Tshr rats due to the suppression of the thyroid specific genes, i.e., thyroperoxidase (Tpo), thyroglobulin (Tg) and sodium iodide symporter (Nis), at both mRNA and protein levels. In conclusion, the Tshr rat serves as a brand new genetic model to study CH in human, and will greatly help to shed light into the development of terminal organs that are sensitive to thyroid hormones.
甲状腺刺激激素受体（TSHR）是一种 G 蛋白偶联受体，对甲状腺的发育和生长很重要。在一些先天性甲状腺功能减退症（CH）患者中发现 TSHR 的移码和/或无义突变，但在动物模型中尚未对其进行功能研究。在本工作中，我们利用 CRISPR/Cas 基因组编辑技术，在大鼠中产生了一种独特的 Tshr 基因敲除模型，该模型可模拟 TSHR Y444X 患者的表型。在这种大鼠模型中，TSHR 在第二跨膜结构域截断，导致 CH 表型，如在患者中观察到的，包括矮小、甲状腺发育不全、不孕、TSH 抵抗以及血清甲状腺激素水平低。在断奶后，用左甲状腺素（L-T4）治疗可部分逆转这些表型。由于甲状腺特异性基因，即甲状腺过氧化物酶（Tpo）、甲状腺球蛋白（Tg）和钠碘转运体（Nis）的 mRNA 和蛋白水平受到抑制，Tshr 大鼠的甲状腺发育严重受损。总之，Tshr 大鼠为研究人类 CH 提供了一个全新的遗传模型，并将极大地有助于阐明对甲状腺激素敏感的终末器官的发育。
