Isolated Methylmalonic Acidemia A Systems Biology Approach to a Monogenic Disorder

Isolated methylmalonic acidemia (MMA) is caused by deficiency of the enzyme methylmalonyl-CoA mutase (MUT). Chronic kidney disease is among the major secondary complications of MMA. In this study, we have re-analysed a microarray dataset to generate a holistic view of MMA-associated renal disease. Methodology: GSE41044 mRNA microarray dataset deposited by Manoli et al was downloaded from the Gene Expression Omnibus (GEO) database. The quality of microarray data was measured by principle component analysis and hierarchical clustering using ggplot2 package of R and ClusterMaker application of Cytoscape 3.2.1, respectively. Using GEO2R tool of GEO, genes with adjusted p-value≤0.05 were assumed as differentially expressed (DE). Using CluePedia plugin version 2.1.7 of Cytoscape, a protein-protein interaction network was constructed and analyzed by Cytoscape NetworkAnalyzer tool and nodes with the highest degree and betweenness centrality parameters were identified. Pathway enrichment analysis was performed using Cytoscape ClueGO plugin version 2.1.7 and signaling pathways with adjusted p-value≤0.05 were determined.Results: In this study, we re-analyzed the GSE41044 microarray dataset which explores kidney mRNA expression profiles from Mut +/+, Mut +/- and Mut -/- mice. In quality analysis steps, the samples were segregated based on their state (homozygous, heterozygous, wild-type), indicating the satisfactory quality of this dataset. The comparison of homozygous and heterozygous with wild-type samples revealed 993 and 10 DE genes, respectively. Moreover, top central genes were identified that they may have critical role in the MMA-associated renal disease. Furthermore, Gene ontology (GO) enrichment analysis resulted in GO terms such as lipid metabolic process and peptide metabolic process which most of them are expected to be associated with MMA pathogenesis. Conclusions: In conclusion, we have here followed a systematic approach to explore the underlying molecular mechanisms of MMA as a monogenic disease. Methods employed in this study may also be used for other monogenic diseases to suggest novel therapies via generation of holistic maps.

کلیدواژه ها:

Bioinformatics ، Gene ontology ، Isolated methylmalonic acidemia ، Microarray ، Protein interaction network.