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Upregulation of GBP1 in thyroid primordium is required for developmental thyroid morphogenesis
Genetics in Medicine ( IF 8.8 ) Pub Date : 2021-06-30 , DOI: 10.1038/s41436-021-01237-3
Rui-Meng Yang 1 , Ming Zhan 1, 2 , Qin-Yi Zhou 3 , Xiao-Ping Ye 1 , Feng-Yao Wu 1 , Mei Dong 1 , Feng Sun 1 , Ya Fang 1 , Rui-Jia Zhang 1 , Chang-Run Zhang 1 , Liu Yang 1 , Miao-Miao Guo 1 , Jun-Xiu Zhang 4 , Jun Liang 5 , Feng Cheng 6 , Wei Liu 1 , Bing Han 1 , Yi Zhou 7, 8 , Shuang-Xia Zhao 1 , Huai-Dong Song 1
Affiliation  

Purpose

Congenital hypothyroidism (CH) is a common congenital endocrine disorder in humans. CH-related diseases such as athyreosis, thyroid ectopy, and hypoplasia are primarily caused by dysgenic thyroid development. However, the underlying molecular mechanisms remain unknown.

Methods

To identify novel CH candidate genes, 192 CH patients were enrolled, and target sequencing of 21 known CH-related genes was performed. The remaining 98 CH patients carrying no known genes were subjected to exome sequencing (ES). The functions of the identified variants were confirmed using thyroid epithelial cells in vitro and in zebrafish model organisms in vivo.

Results

Four pathogenic GBP1 variations from three patients were identified. In zebrafish embryos, gbp1 knockdown caused defective thyroid primordium morphogenesis and hypothyroidism. The thyroid cells were stuck together and failed to dissociate from each other to form individual follicles in gbp1-deficient embryos. Furthermore, defects were restored with wild-type human GBP1 (hGBP1) messenger RNA (mRNA) except for mutated hGBP1 (p.H150Y, p.L187P) overexpression. GBP1 promoted β-catenin translocation into the cytosol and suppressed the formation of cellular adhesion complexes. Suppression of cell–cell adhesion restored the thyroid primordium growth defect observed in gbp1-deficient zebrafish embryos.

Conclusion

This study provides further understanding regarding thyroid development and shows that defective cellular remodeling could cause congenital hypothyroidism.



中文翻译:

甲状腺原基中 GBP1 的上调是发育性甲状腺形态发生所必需的

目的

先天性甲状腺功能减退症(CH)是人类常见的先天性内分泌疾病。CH 相关疾病,如动脉粥样硬化、甲状腺异位和发育不全,主要是由甲状腺发育异常引起的。然而,潜在的分子机制仍然未知。

方法

为了鉴定新的 CH 候选基因,招募了 192 名 CH 患者,并对 21 个已知的 CH 相关基因进行了靶向测序。其余 98 名不携带已知基因的 CH 患者接受外显子组测序 (ES)。使用体外的甲状腺上皮细胞和体内的斑马鱼模型生物证实了已鉴定变体的功能。

结果

鉴定了来自三名患者的四种致病性GBP1变异。在斑马鱼胚胎中,gbp1敲低导致甲状腺原基形态发生缺陷和甲状腺功能减退。甲状腺细胞粘在一起,无法在gbp1 缺陷胚胎中相互分离以形成单独的卵泡。此外,除了突变的hGBP1 (p.H150Y, p.L187P) 过表达外,用野生型人GBP1 ( hGBP1 ) 信使 RNA (mRNA) 修复了缺陷。GBP1 促进 β-catenin 易位进入细胞质并抑制细胞粘附复合物的形成。抑制细胞 - 细胞粘附恢复了在gbp1中观察到的甲状腺原基生长缺陷-缺陷斑马鱼胚胎。

结论

这项研究提供了对甲状腺发育的进一步了解,并表明有缺陷的细胞重塑可能导致先天性甲状腺功能减退。

更新日期:2021-07-01
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