Ubiquitin-protein ligase E3A mRNA (UBE3A mRNA)

Ubiquitin-protein ligase E3A (UBE3A) mRNA is the transcript that encodes the E6AP protein, a critical E3 ubiquitin ligase involved in the degradation of proteins within the proteasome system (UniProt Q05023). In the mammalian brain, the UBE3A gene is subject to genomic imprinting, where the maternal allele is active and the paternal allele is silenced by a long non-coding RNA called the UBE3A antisense transcript (UBE3A-ATS) (PubMed: 22190057). Loss of the maternal UBE3A mRNA expression, often due to chromosomal deletions or mutations, results in Angelman Syndrome, a neurodevelopmental disorder characterized by severe intellectual disability, lack of speech, and a happy demeanor (NIH: MedlinePlus). Conversely, an excess of UBE3A mRNA due to gene duplication is linked to Dup15q syndrome and autism spectrum disorders. Modern therapeutic approaches, such as those using antisense oligonucleotides (ASOs), target the UBE3A-ATS to trigger its degradation, thereby allowing the paternal UBE3A pre-mRNA to be processed into functional mature mRNA (Nature: 2015, 518(7539)). This strategy aims to restore UBE3A protein levels in neurons to treat the underlying cause of Angelman Syndrome. Clinical candidates like GTX-102 and Rugonersen are currently being evaluated for their ability to safely and effectively modulate UBE3A mRNA levels in the central nervous system (ClinicalTrials.gov: NCT04259281).

Other names

UBE3A transcriptUBE3A pre-mRNAE6AP mRNAUbiquitin-protein ligase E3A mRNAUBE3A-ATS

Antisense oligonucleotide-mediated degradation of the UBE3A-ATS (antisense transcript) to restore expression of the paternal UBE3A allele.