1 Institut de Génomique Fonctionnelle de Lyon, Université de Lyon CNRS UMR 5242, INRA USC 1370, Ecole Normale Supérieure de Lyon , Lyon, France .
2 Plateau de Biologie Expérimentale de la Souris SFR Biosciences, Ecole Normale Supérieure de Lyon , Lyon, France .
Thyroid. 2018 Jan;28(1):139-150. doi: 10.1089/thy.2017.0389. Epub 2018 Jan 2.
Resistance to thyroid hormone due to THRA mutations (RTHα) is a recently discovered genetic disease, displaying important variability in its clinical presentation. The mutations alter the function of TRα1, one of the two nuclear receptors for thyroid hormone.
The aim of this study was to understand the relationship between specific THRA mutations and phenotype. CRISPR/Cas9 genome editing was used to generate five new mouse models of RTHα, with frameshift or missense mutations.
Like human patients, mutant mice displayed a hypothyroid-like phenotype, with altered development. Phenotype severity varied between the different mouse models, mainly depending on the ability of the mutant receptor to interact with transcription corepressor in the presence of thyroid hormone.
The present mutant mice represent highly relevant models for the human genetic disease which will be useful for future investigations.
由于 THRA 突变导致的甲状腺激素抵抗（RTHα）是一种新发现的遗传性疾病，其临床表现存在重要的变异性。这些突变改变了甲状腺激素的两个核受体之一 TRα1 的功能。
本研究旨在了解特定 THRA 突变与表型之间的关系。使用 CRISPR/Cas9 基因组编辑技术生成了五个具有移码或错义突变的新的 RTHα 小鼠模型。
与人类患者一样，突变小鼠表现出类似甲状腺功能减退的表型，发育异常。不同的小鼠模型之间表型严重程度存在差异，主要取决于突变受体在甲状腺激素存在的情况下与转录核心抑制因子相互作用的能力。
本研究中的突变小鼠代表了与人类遗传疾病高度相关的模型，将有助于未来的研究。
