Novel THRB mutation analysis in congenital hypothyroidism with thyroid dysgenesis.
Novel THRB mutation analysis in congenital hypothyroidism with thyroid dysgenesis.
复制标题
先天性甲状腺功能减退症伴甲状腺发育不全的新型 THRB 突变分析。
DOI：
10.1002/jcb.27264
复制
发表时间：
2018
影响因子：
4
通讯作者：
Liu Shiguo
中科院分区：
文献类型：
--
作者：
Zhou Zhixia;Yang Chengyu;Lv Fuyan;Liu Wenmiao;Yan Shengli;Zang Hongwei;Li Miaomiao;Wang Fang;Zang Yucui;Liu Shiguo
甲状腺发育不全（TD）占先天性甲状腺功能减退症的大多数病例。虽然甲状腺激素受体β（THRB）的突变已在TD中确定，但THRB的突变谱和表型-基因型相关性尚未完全阐明。本研究旨在寻找THRB基因的突变位点，研究这些突变位点的功能，并试图阐明THRB与TD的关系。因此，我们在中国收集的280例TD患者和200例正常人中筛选了THR的外显子。我们在人甲状腺滤泡上皮细胞（Nthy‐ori细胞系）中进行了细胞形态学分析、MTT分析、流式细胞术分析和定量逆转录聚合酶链反应，以检查THb突变的影响。在两个不相关的患者中，在THRB中发现了两个新的错义突变，c.76G>A（p.D26N）和c.107G>A（p.C36Y）。功能研究表明，C36 Y突变体引起的形态学变化，抑制细胞增殖和促进人甲状腺细胞系的凋亡。此外，我们发现，与野生型相比，在MUCHTRBC中，甲状腺球蛋白（TG）和Na+/I−同向转运体（NIS）的信使RNA表达以时间依赖的方式降低。据我们所知，这是第一项记录中国人群中THb突变患病率和TD基因型-表型谱的研究。我们表征了C36 Y突变的功能，该突变减少了甲状腺上皮细胞的细胞增殖并增加了细胞死亡。本研究为TD的遗传性THRB缺陷和疾病机制提供了进一步的证据。
Thyroid dysgenesis (TD) accounts for most cases of congenital hypothyroidism. Although mutations in thyroid hormone receptor β (THRB) have been identified in TD, the mutational spectrum ofTHRBand phenotype‐genotype correlations have not been fully elucidated. In this study, we aimed to find mutations ofTHRB, examine the functions of these mutations, and attempt to elucidate the relationship betweenTHRBand TD. Thus, we screened the exons ofTHRBin 280 patients with TD and 200 normal subjects in samples collected from China. We performed cell morphology assays, MTT assays, flow cytometric analyses, and a quantitative reverse‐transcription polymerase chain reaction in human thyroid follicular epithelial cells (Nthy‐ori cell line) to examine the impact ofTHRBmutations. In two unrelated patients, two novel missense mutations, c.76G>A (p.D26N) and c.107G>A (p.C36Y), were identified inTHRB. Functional studies suggested that the C36Y mutant caused changes in morphology, inhibiting cell proliferation and promoting apoptosis in a human thyroid cell line. In addition, we found that messenger RNA expressions of thyroglobulin (TG) and the Na+/I−symporter (NIS) were decreased in a time‐dependent manner in mutantTHRBcompared with the wild type. To our knowledge, this is the first study to document the prevalence ofTHRBmutations and the genotype‐phenotype spectrum of TD in a Chinese population. We characterized the function of a C36Y mutation, which reduced cell proliferation and increased cell death in thyroid epithelial cells. This study provides further evidence for geneticTHRBdefects and disease mechanisms in TD.