Cai Guiquan, Yang Xuan, Chen Ting, Jin Fangchun, Ding Jing, Wu Zhenkai
Department of Orthopaedics, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Pediatric Orthopaedics, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
PeerJ. 2020 Jan 20;8:e8422. doi: 10.7717/peerj.8422. eCollection 2020.
As one of the most common major congenital distal skeletal abnormalities, congenital talipes equinovarus (clubfoot) affects approximately one in one thousandth newborns. Although several etiologies of clubfoot have been proposed and several genes have been identified as susceptible genes, previous studies did not further explore signaling pathways and potential upstream and downstream regulatory networks. Therefore, the aim of the present investigation is to explore abnormal pathways and their interactions in clubfoot using integrated bioinformatics analyses.
KEGG, gene ontology (GO), Reactome (REAC), WikiPathways (WP) or human phenotype ontology (HP) enrichment analysis were performed using WebGestalt, g:Profiler and NetworkAnalyst.
A large number of signaling pathways were enriched e.g. signal transduction, disease, metabolism, gene expression (transcription), immune system, developmental biology, cell cycle, and ECM. Protein-protein interactions (PPIs) and gene regulatory networks (GRNs) analysis results indicated that extensive and complex interactions occur in these proteins, enrichment pathways, and TF-miRNA coregulatory networks. Transcription factors such as SOX9, CTNNB1, GLI3, FHL2, TGFBI and HOXD13, regulated these candidate proteins.
The results of the present study supported previously proposed hypotheses, such as ECM, genetic, muscle, neurological, skeletal, and vascular abnormalities. More importantly, the enrichment results also indicated cellular or immune responses to external stimuli, and abnormal molecular transport or metabolism may be new potential etiological mechanisms of clubfoot.
先天性马蹄内翻足作为最常见的主要先天性远端骨骼异常之一，影响约千分之一的新生儿。尽管已经提出了几种先天性马蹄内翻足的病因，并且已经鉴定出几种基因作为易感基因，但先前的研究并未进一步探索信号通路以及潜在的上游和下游调控网络。因此，本研究的目的是使用综合生物信息学分析来探索先天性马蹄内翻足中的异常通路及其相互作用。
使用WebGestalt、g:Profiler和NetworkAnalyst进行KEGG、基因本体论（GO）、Reactome（REAC）、WikiPathways（WP）或人类表型本体论（HP）富集分析。
大量信号通路得到富集，例如信号转导（signal transduction）、疾病（disease）、代谢（metabolism）、基因表达（转录，gene expression (transcription)）、免疫系统（immune system）、发育生物学（developmental biology）、细胞周期（cell cycle）和细胞外基质（ECM）。蛋白质-蛋白质相互作用（PPI）和基因调控网络（GRN）分析结果表明，这些蛋白质、富集通路和TF-miRNA共调控网络中存在广泛而复杂的相互作用。转录因子如SOX9、CTNNB1、GLI3、FHL2、TGFBI和HOXD13调节这些候选蛋白质。
本研究结果支持了先前提出的假设，如细胞外基质、遗传、肌肉、神经、骨骼和血管异常。更重要的是，富集结果还表明细胞或免疫对外界刺激的反应，以及异常的分子转运或代谢可能是先天性马蹄内翻足新的潜在病因机制。
