mycophenolic-acid and Cleft-Palate

Mycophenolate embryopathy (ME) is a congenital malformation induced by mycophenolic acid (MA). Microtia is the most common ME phenotype. This study aimed to identify the key genes in the pathological process of microtia caused by mycophenolate mofetil (MM) through bioinformatics methods, to explore the potential pathogenesis, and to provide a direction for future genetic research on aetiology.. Genes related to MM and microtia were obtained from the GeneCards database for bioinformatics. Metacore was used to identify and visualize the upstream and downstream gene relationships in the protein-protein interaction (PPI) results of these genes. The clusterProfiler R software package was used to simulate and visualize the enrichment results based on data from Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses.. Fifty-nine genes were associated with microtia and MM/MA. The hub genes with the most significant effects on MM/MA-induced microtia pathogenesis included tumour protein P53 (p53), MDM2 proto-oncogene (MDM2), ribosomal protein L5 (RPL5) and ribosomal protein S14 (RBS14). The GO term with the most enriched genes was peptidyl-tyrosine phosphorylation. For the KEGG terms, there was significant enrichment regarding the haematopoietic cell lineage, apoptosis, p53 signalling, proteasome and necroptosis.. We propose that an axis composed of MA, microtia, TP53 and related genes is involved in ME pathogenesis. The important role of TP53-associated ribosome stress in ME pathogenesis is consistent with our previous findings from MA-induced cleft lip and palate. Deregulation of genes protective against TP53 overexpression, such as MDM2, could be a strategy for constructing a microtia animal model.

Topics: Cleft Lip; Cleft Palate; Computational Biology; Congenital Microtia; Humans; Mycophenolic Acid; Protein Interaction Maps; Proto-Oncogene Proteins c-mdm2; Ribosomal Proteins; Ribosomes; Tumor Suppressor Protein p53

Mycophenolate embryopathy (MPE) is a mycophenolic acid (MPA)-induced congenital malformation with distinctive symptoms. Cleft lip/palate (CLP) is one of the most common symptoms of MPE. The aim of this study was to screen and verify hub genes involved in MPA-induced CLP and to explore the potential molecular mechanisms underlying MPE.Overlapping genes related to MPA and CLP were obtained from the GeneCards database. These genes were further analyzed via bioinformatics. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis results were visualized with the Cytoscape ClueGO plug-in. Gene protein-protein interaction (PPI) networks were constructed based on data obtained from the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database.Overall, 58 genes related to MPA and CLP were identified. The genes most relevant to MPA-induced CLP included ABCB1, COL1A1, Rac1, TGFβ1, EDN1, and TP53, as well as the TP53-associated genes MDM2 and RPL5. GO analysis demonstrated gene enrichment regarding such terms as ear, mesenchymal, striated muscle, and ureteric development. KEGG analysis demonstrated gene enrichment in such pathways as the HIF-1 signaling pathway, glycosylphosphatidylinositol-anchor biosynthesis, the TNF signaling pathway, and hematopoietic stem cell development.Bioinformatic analysis was performed on the genes currently known to be associated with MPA-induced CLP pathogenesis. MPA-induced CLP is mediated by multiple ribosome stress related genes and pathways. MDM2, RPL5 and TP53 could be the main contributor in this pathogenesis, along with several other genes. ABCB1 polymorphism could be related to the probability of MPA-induced CLP.

Topics: Cleft Lip; Cleft Palate; Computational Biology; Datasets as Topic; Gene Regulatory Networks; Genetic Predisposition to Disease; Humans; Mycophenolic Acid; Protein Interaction Mapping; Protein Interaction Maps; Proto-Oncogene Proteins c-mdm2; Ribosomal Proteins; Ribosomes; Tumor Suppressor Protein p53