Network-Based Analysis Reveals the Potential Involvement of Proteasome Subunit Alpha-2 in Tetralogy of Fallot

Introduction: tetralogy of fallot (tof) is the most common cyanotic form of congenital heart defects. however, there is no effective therapeutic approach and current therapies have limited curative efficacy. moreover, the exact etiology of tof has remained largely unknown. improved understanding of molecular mechanisms can give an insight into tof pathogenesis and development of therapeutic approaches. methods: here, we conducted a systematic study on the right ventricular myocardium of 24 infants (16 tof/8 control) using weighted gene co-expression network analysis (wgcna) to identify meaningful modules or candidate biomarkers. results: co-expression network analysis by wgcna suggested that a highly preserved turquoise module with 2,493 genes and a p-value of 3×10-11 was significantly correlated to tof. the top 5 hub genes of this module were psma2, myl12a, c11orf71, commd6, and creg1. the result of turquoise module enrichment showed that the most correlation topic in biological processes and kegg pathways were positive regulation of cardiac neural crest migration involved in outflow tract morphogenesis and positive regulation of neural crest cell differentiation. also, we recognized 4 fda-approved drug candidates for other indications could potentially use for the treatment of tof patients through regulation of two hub genes of the coexpression network (psma2 and ndufa4). our findings also showed that the 13 experimentally validated micrornas regulated the co-expression network through 5 hub genes. conclusion: we systematically recognized co-expressed gene modules and hub genes associated with tof progression, which offered insights into the mechanisms underlying tof progression and some potential drugs for the treatment of tof.