Next-generation sequencing of NKX2.1, FOXE1, PAX8, NKX2.5, and TSHR in 100 Chinese patients with congenital hypothyroidism and athyreosis
Next-generation sequencing of NKX2.1, FOXE1, PAX8, NKX2.5, and TSHR in 100 Chinese patients with congenital hypothyroidism and athyreosis
复制标题
100 名中国先天性甲状腺功能减退症和动脉粥样硬化患者的 NKX2.1、FOXE1、PAX8、NKX2.5 和 TSHR 新一代测序
DOI：
10.1016/j.cca.2017.04.020
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发表时间：
2017-07-01
影响因子：
5
通讯作者：
Gu, Maosheng
中科院分区：
文献类型：
--
作者：
Wang, Fang;Liu, Chang;Gu, Maosheng
背景：某些转录因子（NKX2.1、FOXE1、NKX2.5和PAX8）和促甲状腺激素受体（TSHR）基因的异常表达与甲状腺机能不良（TD）相关。我们的目的是在中国人群中确定CH合并athyreosis患者的候选基因突变，并建立基因型-表型相关性。方法：通过下一代测序筛选NKX2.1、FOXE1、NKX2.5、PAX8和TSHR的轴突和侧翼序列，并通过直接Sanger测序进一步确认。计算突变频率并与数据库进行比较。还确定了基因型与表型之间的关系。结果：tshrp检测到7种变异。P52T、p.G132R、p.M164K、p.R450H、p.C700E、p.A522V、p.R528Sp. G132R, p. M164K和p. R528S变体首先在公共数据库中确定。在NKX2.1中检测到5个变异（p.G44D、p.G360V、p.R401Q、p.L418I和p.E453Q），在FOXE1中检测到1个变异（p.P243T）。此外，在NKX2.5中发现了一个变体（p.N291I），在PAX8中发现了两个变体（p.A355V和c. -26G > A）。结论：我们的研究表明TSHR突变具有表型变异性，进一步扩大了TSHR的突变谱。我们还发现NKX2.1、FOXE1、NKX2.5和PAX8在CH和athreosis患者中的突变率较低，而TSHR的突变率较高。
Background: The abnormal expression of certain transcription factors (NKX2.1, FOXE1, NKX2.5, and PAX8) and thyroid stimulating hormone receptor (TSHR) genes has been associated with athyreosis, which is a form of thyroid dysgenesis (TD). We aimed to identify candidate gene mutations in CH patients with athyreosis and to establish the genotype-phenotype correlations in a Chinese population.Methods: The axons and flanking sequences of NKX2.1, FOXE1, NKX2.5, PAX8, and TSHR were screened by next generation sequencing and further confirmed by direct Sanger sequencing. The mutation frequencies were calculated and compared against databases. The relationship between genotype and phenotype was also determined.Results: Seven variants were detected in TSHR-p.P52T, p.G132R, p.M164K, p.R450H, p.C700E, p.A522V, and p.R528S. The p. G132R, p. M164K and p. R528S variants were first identified in public databases. Five variants (p.G44D, p.G360V, p.R401Q, p.L418I, and p.E453Q) were found in NKX2.1 and one variant (p.P243T) was detected in FOXE1. In addition, one variant (p.N291I) was found in NKX2.5 and two variants (p.A355V and c. -26G > A) were detected in PAX8.Conclusions: Our study indicated that TSHR mutations have phenotypic variability and has further expanded the mutation spectrum of TSHR. We also revealed that the rate of NKX2.1, FOXE1, NKX2.5, and PAX8 mutations were low in patients with CH and athyreosis, in contrast to the higher rate of TSHR mutations.