UBE3A

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.

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.