Department of Plastic, Reconstructive and Hand Surgery, Amsterdam UMC, Amsterdam Medical Centre, Amsterdam, the Netherlands; Plastic Surgery Hospital, Peking Union Medical College, Beijing, China.
Department of Plastic, Reconstructive and Hand Surgery, Amsterdam UMC, Amsterdam Medical Centre, Amsterdam, the Netherlands.
Int J Pediatr Otorhinolaryngol. 2021 Dec;151:110916. doi: 10.1016/j.ijporl.2021.110916. Epub 2021 Sep 11.
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.
麦考酚酸（mycophenolic acid，MA）所致霉酚酸胚胎病（mycophenolate embryopathy，ME）为一先天性畸形。小耳畸形是 ME 最常见的表型。本研究旨在通过生物信息学方法鉴定霉酚酸酯（mycophenolate mofetil，MM）致小耳畸形的病理过程中的关键基因，探索潜在的发病机制，为未来病因学的遗传研究提供方向。
从基因数据库中获取与 MM 和小耳畸形相关的基因，利用 Metacore 软件对这些基因的蛋白-蛋白相互作用（protein-protein interaction，PPI）结果进行上游和下游基因关系的识别和可视化。采用 clusterProfiler R 软件包对基于基因本体论（gene ontology，GO）和京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes，KEGG）分析数据的富集结果进行模拟和可视化。
共鉴定出与小耳畸形和 MM/MA 相关的 59 个基因。对 MM/MA 诱导小耳畸形发病机制影响最大的核心基因包括肿瘤蛋白 P53（p53）、MDM2 原癌基因（MDM2）、核糖体蛋白 L5（RPL5）和核糖体蛋白 S14（RBS14）。GO 术语中富集基因最多的是肽基酪氨酸磷酸化。KEGG 术语中，造血细胞谱系、细胞凋亡、p53 信号转导、蛋白酶体和坏死性凋亡显著富集。
我们提出，由 MA、小耳畸形、TP53 和相关基因组成的轴参与 ME 的发病机制。在 MA 诱导的唇腭裂中，我们之前发现的与核糖体应激相关的 TP53 重要作用与 ME 发病机制一致。MDM2 等保护 TP53 过表达的基因失稳可能是构建小耳畸形动物模型的一种策略。
