Novel Missense Variants in PAX8 and NKX2-1 Cause Congenital Hypothyroidism.
Novel Missense Variants in PAX8 and NKX2-1 Cause Congenital Hypothyroidism.
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DOI：
10.3390/ijms24010786
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发表时间：
2023-01-02
影响因子：
5.6
通讯作者：
Liang, Desheng
中科院分区：
文献类型：
--
作者：
Li, Menglin;Li, Zhuo;Chen, Miaomiao;Hu, Zhiqing;Zhou, Miaojin;Wu, Lingqian;Zhang, Chunhua;Liang, Desheng
关键词：
原发性先天性甲状腺功能减退症（CH）是一种常见的新生儿内分泌疾病，其特征是促甲状腺激素（TSH）浓度升高和游离甲状腺素（FT 4）浓度降低。PAX 8和NKX 2 -1是参与甲状腺发育的重要转录因子。在这项研究中，我们通过全外显子组测序（WES）在三名具有可变表型的无关CH患者中检测到PAX 8（c.149A > C和c.329G > A）和NKX 2 -1（c.706A > G）的三种新变体。Western blot和免疫荧光分析结果表明，三种变异体对蛋白表达和亚细胞定位均无影响。然而，电泳迁移率变动分析（EMSA）和双荧光素酶报告基因分析的结果表明，PAX 8和NKX 2 -1中的三种变体都影响了它们的DNA结合能力，降低了它们的反式激活能力。此外，通过双荧光素酶报告基因测定确定了K236 E − NKX 2 -1中的显性负效应。综上所述，我们的研究结果扩展了我们对PAX 8和NKX 2 -1当前突变谱的了解，并为诊断，治疗和预防这些家庭中的CH提供了重要信息。
Primary congenital hypothyroidism (CH) is a common neonatal endocrine disorder characterized by elevated concentrations of thyroid stimulating hormone (TSH) and low concentrations of free thyroxine (FT4). PAX8 and NKX2-1 are important transcription factors involved in thyroid development. In this study, we detected three novel variants in PAX8 (c.149A > C and c.329G > A) and NKX2-1 (c.706A > G) by whole exome sequencing (WES) in three unrelated CH patients with variable phenotypes. The results of Western blot and immunofluorescence analysis showed that the three variants had no effect on protein expression and subcellular localization. However, the results of the electrophoretic mobility shift assay (EMSA) and dual-luciferase reporter assay suggested that the three variants in PAX8 and NKX2-1 both affected their DNA-binding ability and reduced their transactivation capacity. Moreover, a dominant-negative effect in K236E−NKX2-1 was identified by dual-luciferase reporter assay. To sum up, our findings extend our knowledge of the current mutation spectrum of PAX8 and NKX2-1 and provide important information for diagnosing, treating, and preventing CH in these families.
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DOI：
10.1016/j.beem.2018.05.002
发表时间：
2018-08-01
影响因子：
7.4
作者：
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影响因子：
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影响因子：
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通讯作者：
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