The UBE3A gene provides instructions for making a protein called ubiquitin protein ligase E3A. Ubiquitin protein ligases are enzymes that target other proteins to be broken down (degraded) within cells. These enzymes attach a small molecule called ubiquitin to proteins that should be degraded. Cellular structures called proteasomes recognize and digest these ubiquitin-tagged proteins. Protein degradation is a normal process that removes damaged or unnecessary proteins and helps maintain the normal functions of cells.
Studies suggest that ubiquitin protein ligase E3A plays a critical role in the normal development and function of the nervous system. Studies suggest that it helps control (regulate) the balance of protein synthesis and degradation (proteostasis) at the junctions between nerve cells (synapses) where cell-to-cell communication takes place. Regulation of proteostasis is important for the synapses to change and adapt over time in response to experience, a characteristic called synaptic plasticity. Synaptic plasticity is critical for learning and memory.
People normally inherit two copies of the UBE3A gene, one from each parent. Both copies of the gene are turned on (active) in most of the body's tissues. However, in nerve cells (neurons) in the brain and spinal cord (the central nervous system), only the copy inherited from a person's mother (the maternal copy) is active. This parent-specific gene activation results from a phenomenon known as genomic imprinting.
Health Conditions Related to Genetic Changes
A loss of UBE3A gene function in the brain likely causes many of the characteristic features of Angelman syndrome, a complex genetic disorder that primarily affects the nervous system. This loss of function results from a chromosomal change or gene variant (also known as a mutation) that affects the maternal copy of the gene.
Several different genetic mechanisms can turn off (inactivate) or delete the UBE3A gene. Most cases of Angelman syndrome (about 70 percent) occur when a segment of the maternal chromosome 15 containing this gene is deleted. In another 10 to 20 percent of cases, Angelman syndrome results from variants within the UBE3A gene itself. Most of these variants lead to the production of an abnormally short, nonfunctional version of ubiquitin protein ligase E3A. Because the copy of the gene inherited from a person's father (the paternal copy) is normally inactive in most areas of the brain, loss of the maternal copy prevents any of the enzyme from being produced in these brain regions. This lack of enzyme function likely causes the major signs and symptoms of Angelman syndrome.
Other abnormalities involving the region of chromosome 15 that contains the UBE3A gene can also cause Angelman syndrome. These chromosomal changes include rearrangements (translocations) of genetic material or a defect in the region of DNA that controls activation of the UBE3A gene. Like variants within the gene, these chromosomal changes prevent any functional ubiquitin protein ligase E3A from being produced in certain parts of the brain.More About This Health Condition
Variants in the UBE3A gene have been found in a small number of individuals with a variety of neurological problems, including intellectual disability, seizures, and autism spectrum disorder. Unlike variants involved in Angelman syndrome, which reduce the function of ubiquitin protein ligase E3A in cells, these rare variants increase the function of the protein. It is not clear how excess ubiquitin protein ligase E3A activity affects development and contributes to the neurological features in people with these variants.
Other Names for This Gene
- CTCL tumor antigen se37-2
- E6AP ubiquitin-protein ligase
- human papilloma virus E6-associated protein
- oncogenic protein-associated protein E6-AP
- ubiquitin protein ligase E3A (human papilloma virus E6-associated protein, Angelman syndrome)
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
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- Louros SR, Osterweil EK. Perturbed proteostasis in autism spectrum disorders. J Neurochem. 2016 Dec;139(6):1081-1092. doi: 10.1111/jnc.13723. Epub 2016 Aug 4. Citation on PubMed or Free article on PubMed Central
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- Moncla A, Malzac P, Livet MO, Voelckel MA, Mancini J, Delaroziere JC, Philip N, Mattei JF. Angelman syndrome resulting from UBE3A mutations in 14 patients from eight families: clinical manifestations and genetic counselling. J Med Genet. 1999 Jul;36(7):554-60. Citation on PubMed or Free article on PubMed Central
- Noor A, Dupuis L, Mittal K, Lionel AC, Marshall CR, Scherer SW, Stockley T, Vincent JB, Mendoza-Londono R, Stavropoulos DJ. 15q11.2 Duplication Encompassing Only the UBE3A Gene Is Associated with Developmental Delay and Neuropsychiatric Phenotypes. Hum Mutat. 2015 Jul;36(7):689-93. doi: 10.1002/humu.22800. Citation on PubMed
- Singhmar P, Kumar A. Angelman syndrome protein UBE3A interacts with primary microcephaly protein ASPM, localizes to centrosomes and regulates chromosome segregation. PLoS One. 2011;6(5):e20397. doi: 10.1371/journal.pone.0020397. Epub 2011 May 25. Citation on PubMed or Free article on PubMed Central
- Tan WH, Bacino CA, Skinner SA, Anselm I, Barbieri-Welge R, Bauer-Carlin A, Beaudet AL, Bichell TJ, Gentile JK, Glaze DG, Horowitz LT, Kothare SV, Lee HS, Nespeca MP, Peters SU, Sahoo T, Sarco D, Waisbren SE, Bird LM. Angelman syndrome: Mutations influence features in early childhood. Am J Med Genet A. 2011 Jan;155A(1):81-90. doi: 10.1002/ajmg.a.33775. Citation on PubMed or Free article on PubMed Central
- Yi JJ, Berrios J, Newbern JM, Snider WD, Philpot BD, Hahn KM, Zylka MJ. An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A. Cell. 2015 Aug 13;162(4):795-807. doi: 10.1016/j.cell.2015.06.045. Epub 2015 Aug 6. Citation on PubMed or Free article on PubMed Central