Ubiquitin protein ligase E3A antisense RNA (UBE3A-ATS)

The Ubiquitin protein ligase E3A antisense RNA (UBE3A-ATS) is a long non-coding RNA (lncRNA) that mediates the paternal silencing of the UBE3A gene in neurons through transcriptional interference (Meng et al., 2015, Nature). In the mammalian brain, UBE3A is subject to genomic imprinting, where the maternal allele is active and the paternal allele is silenced by the antisense expression of UBE3A-ATS. Angelman syndrome (AS) is a severe neurodevelopmental disorder resulting from the loss of the maternal UBE3A allele, which leaves the brain with a deficiency of functional UBE3A protein (Silva-Santos et al., 2015, Journal of Neurodevelopmental Disorders). The specific genomic locus between the UBE3A 3’ UTR and the Snord115 cluster is a critical target for therapeutic intervention, as it represents the region where the antisense transcript overlaps with the sense gene. Therapeutic strategies, primarily antisense oligonucleotides (ASOs) like GTX-102 and Rugonersen, are designed to bind to this region and trigger the RNase H-mediated degradation of UBE3A-ATS (Milazzo et al., 2021, Genes). By reducing the levels of this inhibitory transcript, these therapies aim to unsilence the paternal UBE3A allele and restore protein expression to therapeutic levels in the central nervous system.

Other names

UBE3A-ASUBE3A antisense transcriptSNHG14LNCRNA-UBE3A-ASSNURF-SNRPN-UBE3A-AS

Antisense oligonucleotide-mediated degradation of UBE3A-ATS to restore paternal UBE3A expression