UBE2A is an E2 ubiquitin-conjugating enzyme that transfers ubiquitin from E1 to E3 ligases, catalyzing both Lys-11 and Lys-48-linked polyubiquitination 1. In transcriptional regulation, UBE2A works with E3 enzyme BRE1 to monoubiquitinate histone H2B at Lys-120, creating H2BK120ub1—a critical epigenetic mark for transcriptional activation and RNA polymerase II elongation 2. UBE2A regulates mitophagy by conjugating ubiquitin onto mitochondrial proteins in partnership with Parkin, essential for clearing dysfunctional mitochondria and maintaining neuronal function 3. It also participates in N-end rule-dependent protein degradation through association with E3 ligase UBR4, with its specific recruitment mediated by a distinct hemiRING-UZI module within UBR4 4. Clinically, UBE2A mutations cause X-linked intellectual developmental disorder, Nascimento-type (MRXSN), characterized by moderate-to-severe intellectual disability (100% of cases), speech and language impairment (97%), and dysmorphic facial features (94%) 5. Gene mutations account for 65% of cases while large segment deletions comprise 35% 5. Additionally, UBE2A mutations have been identified as novel candidate driver genes in endometrial polyp development 6, suggesting roles beyond neurodevelopment. Early genetic diagnosis enables optimal prenatal and postnatal management to improve outcomes 5.