Upregulation of GBP1 in thyroid primordium is required for developmental thyroid morphogenesis

Ruimeng Yang ,Yi Zhou,Shuang‐Xia Zhao ,Yun Fang ,Feng Cheng,Ruijia Zhang ,Qianxiang Zhou ,Feng Sun,Liu Yang,Feng‐Yao Wu ,Ming Zhan,Mei Dong,Jun Liang,Chang-Run Zhang,Junxiu Zhang ,Miaomiao Guo ,Xiaoping Ye ,Wei Liu,Bing Han,Hwangjun Song

doi:10.1038/s41436-021-01237-3

Abstract

PurposeCongenital 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. MethodsTo 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. ResultsFour 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. ConclusionThis study provides further understanding regarding thyroid development and shows that defective cellular remodeling could cause congenital hypothyroidism.

Highlights

Congenital hypothyroidism (CH) is the most common inherited endocrine disorder, affecting approximately 1 in 3,000–4,000 newborns worldwide [1,2,3,4]
Using methylation-specific polymerase chain reaction (PCR), this study found that the CpG site of GBP1 was hypermethylated in the genomic DNA isolated from probands CH 90 and CH 168 compared with their euthyroid parents, who carried the same variation (Fig. S1A and S1B)
Thyroid dysgenesis is a consequence of abnormal thyroid gland organogenesis and includes athyreosis (20–30%), ectopic thyroid gland (50–60%), and hypoplasia (5%)

Summary

Introduction

Congenital hypothyroidism (CH) is the most common inherited endocrine disorder, affecting approximately 1 in 3,000–4,000 newborns worldwide [1,2,3,4]. Untreated congenital hypothyroidism inevitably leads to cretinism, causing irreversible brain dysfunction and dwarfism. The majority of CH diseases are caused by thyroid dysgenesis (TD) in the White population, which may manifest as athyreosis, thyroid ectopy, hypoplasia, or hemiagenesis [5, 6]. These diseases are due to embryonic thyroid development defects. The pathogenic variants in these genes only explain a minority of TD patients, suggesting that unknown genetic and epigenetic factors might play important roles in thyroid development [10, 11]

Methods

Results

Conclusion