UBE3A Isoform Biology in Health and Disease
Heather Born
Published November 1, 2025
https://doi.org/10.65856/PXSD5368
KEYWORDS: UBE3A, isoforms, Angelman syndrome, expression, subcellular localization, function, neuron,translational science, human, mouse, gene therapy, development.
ABSTRACT: Ubiquitin protein ligase E3A (UBE3A) is expressed in neurons throughout the brain and is critical for normal neuronal morphology and synaptic function. Altered UBE3A expression is implicated in several neurological disorders, most notably Angelman syndrome (AS), a rare enetic, non-degenerative, neurodevelopmental disorder that results from disruption of the maternal allele of UBE3A due to deletion, mutation, uniparental disomy, or imprinting center defect and leads to loss of neuronal UBE3A protein expression. Multiple isoforms of UBE3A are generated from the human gene sequence, and closely conserved mouse homologs show high sequence identity. Recent findings from the past few years using animal and cellular models, as well as insights from clinical studies in individuals with AS, have been instrumental for identifying isoform-dependent differences in expression, subcellular localization, structure, and contributions to both normal neuronal function and AS-related phenotypes. In this review, the current knowledge on the isoform-specific roles of UBE3A in normal physiology and disease pathology are summarized. Importantly, increased understanding of isoform-specific research questions will be informative for guiding future development of therapeutic strategies.