Wang Fang, Liu Chang, Jia Xiuhua, Liu Xiangju, Xu Yinglei, Yan Shengli, Jia Xuewen, Huang Zuzhou, Liu Shiguo, Gu Maosheng
Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China; Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China.
Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China.
Clin Chim Acta. 2017 Jul;470:36-41. doi: 10.1016/j.cca.2017.04.020. Epub 2017 Apr 25.
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.
The exons 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.
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.
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.
某些转录因子（NKX2.1、FOXE1、NKX2.5和PAX8）以及促甲状腺激素受体（TSHR）基因的异常表达与甲状腺缺如有关，甲状腺缺如是甲状腺发育不全（TD）的一种形式。我们旨在鉴定先天性甲状腺功能减退（CH）合并甲状腺缺如患者的候选基因突变，并在中国人群中建立基因型与表型的相关性。
采用二代测序技术对NKX2.1、FOXE1、NKX2.5、PAX8和TSHR的外显子及侧翼序列进行筛选，并通过直接桑格测序进一步确认。计算突变频率并与数据库进行比较。同时确定基因型与表型之间的关系。
在TSHR中检测到7个变异，分别为p.P52T、p.G132R、p.M164K、p.R450H、p.C700E、p.A522V和p.R528S。p.G132R、p.M164K和p.R528S变异首次在公共数据库中被鉴定。在NKX2.1中发现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1个变异（p.N291I），在PAX8中检测到2个变异（p.A355V和c.-26G>A）。
我们的研究表明TSHR突变具有表型变异性，并进一步扩展了TSHR的突变谱。我们还发现，与TSHR较高的突变率相比，CH合并甲状腺缺如患者中NKX2.1、FOXE1、NKX2.5和PAX8的突变率较低。
