Congenital hypothyroidism (CH) is one of the most prevalent endocrine diseases, for which the underlying mechanisms remain unknown; it is often accompanied by anemia and immunodeficiency in patients. Here, we created a severe CH model together with anemia and T lymphopenia to mimic the clinical features of hypothyroid patients by ethylnitrosourea (ENU) mutagenesis in Bama miniature pigs. A novel recessive c.1226A>G transition of the dual oxidase 2 (DUOX2) gene was identified as the causative mutation. This mutation hindered the production of hydrogen peroxide (H₂O₂) and thus contributed to thyroid hormone (TH) synthesis failure. Transcriptome sequencing analysis of the thymuses showed that Krüppel-like factor 9 (KLF9) was predominantly downregulated in hypothyroid mutants. KLF9 was verified to be directly regulated by TH in a TH receptor (TR)-dependent manner both in vivo and in vitro. Furthermore, knockdown of klf9 in zebrafish embryos impaired hematopoietic development including erythroid maturation and T lymphopoiesis. Our findings suggest that the TR-KLF9 axis is responsible for the hematopoietic dysfunction and might be exploited for the development of novel therapeutic interventions for thyroid diseases.

先天性甲状腺功能减退症（CH）是最流行的内分泌疾病之一，其内在机制尚不清楚。患者常伴有贫血和免疫缺陷。在这里，我们创建了一个严重的CH模型以及贫血和T淋巴细胞减少症，以通过乙亚硝基脲（ENU）诱变在巴马小型猪中模拟甲状腺功能减退患者的临床特征。双重隐性氧化酶2（DUOX2）基因的新型隐性c.1226A> G过渡被确定为致病突变。该突变阻碍了过氧化氢（H ₂ O ₂）的产生，因此导致甲状腺激素（TH）合成失败。胸腺的转录组测序分析表明，Krüppel样因子9（KLF9）在甲状腺功能低下的突变体中主要被下调。证实KLF9在体内和体外均受TH以TH受体（TR）依赖性方式直接调节。此外，在斑马鱼胚胎中敲低klf9会损害造血发育，包括红系成熟和T淋巴细胞生成。我们的发现表明，TR-KLF9轴是造血功能障碍的原因，并可能被用于开发甲状腺疾病的新型治疗手段。