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Integrated bioinformatics analysis of potential pathway biomarkers using abnormal proteins in clubfoot
Guiquan Cai1, Xuan Yang2, Ting Chen2
1Department of Orthopaedics, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Insights
This study reveals complex molecular interactions and signaling pathways involved in congenital talipes equinovarus (clubfoot). New potential causes include immune responses and abnormal metabolism, expanding our understanding of this common birth defect.
Area of Science:
- Genetics and Developmental Biology
- Bioinformatics and Systems Biology
Background:
- Congenital talipes equinovarus (clubfoot) is a frequent congenital skeletal abnormality affecting ~1 in 1000 newborns.
- Existing research identified susceptible genes but lacked comprehensive analysis of signaling pathways and regulatory networks.
Purpose of the Study:
- To investigate abnormal molecular pathways and their interactions in clubfoot using integrated bioinformatics.
- To identify potential upstream and downstream regulatory networks contributing to clubfoot etiology.
Main Methods:
- Utilized WebGestalt, g:Profiler, and NetworkAnalyst for enrichment analysis (KEGG, GO, Reactome, WikiPathways, Human Phenotype Ontology).
- Performed protein-protein interaction (PPI) and gene regulatory network (GRN) analyses.
Main Results:
- Enriched pathways include signal transduction, metabolism, gene expression, immune system, and extracellular matrix (ECM).
- Identified complex interactions within proteins, pathways, and TF-miRNA coregulatory networks.
- Key transcription factors SOX9, CTNNB1, GLI3, FHL2, TGFBI, and HOXD13 were found to regulate candidate proteins.
Conclusions:
- Results support existing hypotheses on ECM, genetic, muscle, neurological, skeletal, and vascular abnormalities in clubfoot.
- New potential etiological mechanisms include cellular/immune responses to stimuli and abnormal molecular transport or metabolism.
Background:
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.
Methods:
KEGG, gene ontology (GO), Reactome (REAC), WikiPathways (WP) or human phenotype ontology (HP) enrichment analysis were performed using WebGestalt, g:Profiler and NetworkAnalyst.
Results:
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.
Conclusion:
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.
