TY - JOUR
T1 - The important role of RPS14, RPL5 and MDM2 in TP53-associated ribosome stress in mycophenolic acid-induced microtia
AU - Lin, Yangyang
AU - Breugem, Corstiaan C.
AU - Maas, Saskia M.
AU - de Bakker, Bernadette S.
AU - Li, Gaofeng
N1 - Funding Information: This work was supported by China Scholarship Council (number 202107720090 ), and Chinese Academy of Medical Sciences Innvation Fund for Medical Science ( CIFMS number 2016-I2M-1–002 ). Publisher Copyright: © 2021
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Objective: 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. Methods: 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. Results: 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. Conclusions: 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.
AB - Objective: 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. Methods: 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. Results: 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. Conclusions: 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.
KW - Bioinformatics
KW - Microtia
KW - Mycophenolic acid
UR - http://www.scopus.com/inward/record.url?scp=85114999973&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ijporl.2021.110916
DO - https://doi.org/10.1016/j.ijporl.2021.110916
M3 - Article
C2 - 34537545
SN - 0165-5876
VL - 151
JO - International Journal of Pediatric Otorhinolaryngology
JF - International Journal of Pediatric Otorhinolaryngology
M1 - 110916
ER -