UBE3A is a gene located on chromosome 15 that encodes the E3 ubiquitin ligase, UBE3A. It is also known as E6-associated protein, or E6AP. This region on chromosome 15 has been linked to both autism and the related disorder, Angelman syndrome.
UBE3A was originally identified in epithelial cell lines1. Subsequent studies demonstrated that in neurons, the copy of UBE3A on the male chromosome is silenced, a process called paternal imprinting. In neurons, UBE3A is expressed solely from the maternal copy of the gene2,3,4.
Paternal imprinting of UBE3A is predominantly thought to arise from expression of a large (0.5-1.0 Mb) antisense RNA transcript that is expressed from the paternal allele, known as the UBE3A-antisense transcript. In other regions of the body, UBE3A is mostly bi-allelically expressed, meaning that it is expressed from both the maternal and paternal copies of the gene.
UBE3A has been shown to function as an E3 ubiquitin ligase. It contains a HECT domain, which is essential for its E3 ligase activity5. UBE3A ubiquitinates certain proteins, termed substrates, and leads to their degradation via the ubiquitin proteasome system. Multiple substrates have been identified for UBE3A, including p536, HHR23A7, p278, and brain-enriched molecules such as ARC9 and Ephexin-510.
UBE3A has also been hypothesized to function as a steroid coactivator in a manner independent of its E3 ligase activity11,12, suggesting that it also plays a role in gene transcription. The elucidation of additional UBE3A substrates in the brain is of high interest.
In the brain, UBE3A levels control communication at synapses and its expression is associated with morphological changes in neuronal architecture, such as changes in synapse number in both humans and animal models13,14,15. UBE3A is also believed to contribute to learning and memory, and disruption of UBE3A is thought to cause circuit imbalance in the brain16,17,18.
Most of these findings have been described through the study of animal models for Angelman syndrome. The synaptic, biochemical and morphological changes caused by the loss of UBE3A in these model systems may be associated with cognitive deficits seen in individuals with Angelman syndrome and possibly autism.
Relevance to autism:
Mutations or deletions within or surrounding UBE3A have been associated with the genetic disorder Angelman syndrome19. The most common cause of Angelman syndrome is a deletion of the maternal chromosome region 15q11-q13, which includes the UBE3A gene. Mutations in the maternal UBE3A gene alone are sufficient to cause Angelman syndrome. Moreover, maternal duplications containing the UBE3A gene are associated with autism20,21. A reduction in UBE3A expression has also been associated with cancer progression and development22.
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- 4 December 2020 (11:09am) (Most Recent) (Selected Revision) by nphillips