Paternal UBE3A antisense transcript locus (UBE3A-ATS) (UBE3A-ATS)

The target is the genomic DNA and the associated long non-coding RNA (lncRNA) known as UBE3A-ATS (Antisense Transcript) located on the paternal chromosome 15q11.2-q13 (Meng et al., 2015). In the mammalian brain, the UBE3A gene is subject to genomic imprinting, where the maternal allele is expressed and the paternal allele is silenced (Silva-Santos et al., 2015). This silencing is mediated by the UBE3A-ATS transcript, which is a very long RNA that overlaps the UBE3A gene in the antisense direction, preventing its transcription on the paternal chromosome (Wolter et al., 2020). Angelman syndrome (AS) results from the loss of the maternal UBE3A allele, leaving neurons with no functional UBE3A protein (PubMed: 25470045). The paternal UBE3A-ATS locus, particularly the region between the Ube3a 3′ UTR and the Snord115 gene cluster, serves as a therapeutic target for antisense oligonucleotides (ASOs) (Meng et al., 2015). These ASOs are designed to bind to and trigger the degradation of the UBE3A-ATS transcript or interfere with its transcription (Ultragenyx, 2024). Successful targeting of this locus leads to the unsilencing or reactivation of the paternal UBE3A gene (Roche, 2023). This reactivation allows for the production of functional UBE3A protein from the paternal allele, potentially ameliorating the symptoms of Angelman syndrome (Silva-Santos et al., 2015). Clinical candidates such as Rugonersen and GTX-102 are currently being evaluated for their ability to modulate this target (ClinicalTrials.gov).

Other names

UBE3A-ASSNHG14Paternal UBE3A locusUBE3A antisense RNAUbe3a-ATS

Antisense oligonucleotide-mediated degradation or transcriptional interference of the UBE3A-ATS transcript to reactivate the silenced paternal UBE3A allele.