Cross-species transcriptomic analysis reveals a conserved miRNA signature targeting MMUT in methylmalonic acidemia:...

Methylmalonic acidemia (MMA) is a rare inborn error of metabolism caused by MMUT deficiency, leading to severe neurological and metabolic complications. This study aimed to identify a core gene signature involved in MMA pathogenesis and to discover evolutionarily conserved microRNA (miRNA) regulators targeting MMUT by integrating human and mouse transcriptomic data. Microarray datasets for Homo sapiens (GSE120683) and Mus musculus (GSE41044, GSE118862) were analyzed using bioinformatic approaches. Differential gene expression (DEG) analysis was performed using the limma package (P < 0.05), and cross-species common genes were identified. Functional enrichment analyses (GO and KEGG) revealed affected pathways. miRNAs targeting MMUT were screened using multiMiR, followed by sequence-based conservation analysis. A total of 1,098 DEGs in human data and a core signature of 60 common genes in mouse models were identified. Functional analysis demonstrated that wound healing, kidney development, PI3K-Akt, and MAPK signaling pathways were commonly affected in both species. miRNA analysis revealed 17 evolutionarily conserved miRNAs with 100% sequence identity in both humans and mice. Notably, miR-181d-5p was identified to directly and specifically bind to the 3' UTR region of the MMUT mRNA through in silico validation. This finding highlights miR-181d-5p as a critical upstream regulator in the molecular pathogenesis of the disease. This study provides one of the first comprehensive analyses integrating transcriptional and post-transcriptional mechanisms in MMA. The identified conserved miRNA network, particularly the MMUT-specific miR-181d-5p, offers novel biomarkers for diagnosis and monitoring while presenting a promising target for RNA-based therapeutic interventions.

The online version contains supplementary material available at 10.1007/s40203-026-00591-x.