Hyperactivitation of UBE3A Gene Causes Autism

Last December, researchers identified more than 1,000 gene mutations in individuals with autism, but how these mutations increased risk for autism was unclear. Now, UNC School of Medicine researchers are the first to show how one of these mutations disables a molecular switch in one of these genes and causes autism.

Published today in the journal Cell, the research shows that an enzyme called UBE3A can be switched off when a phosphate molecule is tacked onto UBE3A. In neurons and during normal brain development, this switch can be turned off and on, leading to tight regulation of UBE3A. But a research team led by Mark Zylka, PhD, associate professor of cell biology and physiology, found that an autism-linked mutation destroys this regulatory switch. Destruction of the switch creates an enzyme that cannot be turned off. As a result, UBE3A becomes hyperactive and drives abnormal brain development and autism.

"Genetic studies are showing that there will be about 1,000 genes linked to autism. This means you could mutate any one of them and get the disorder. We found how one of these mutations works," said Zylka, senior author of the Cell paper and member of the UNC Neuroscience Center.

The work was done in human cell lines, as well as mouse models.

Because this one autism-linked UBE3A mutation was part of the Simons Simplex Collection - and Zylka previously had been funded through a Simons Foundation grant - he had access to the cells that were used to find this one mutation. When Jason Yi, PhD, a postdoctoral fellow in Zylka's lab, sequenced the genes from the cell samples - including cells from the child's parents - he found that the parents had no hyperactive UBE3A but the child did.

The child's regulatory switch was broken, causing UBE3A to be perpetually switched on.

"When this child's mutation was introduced into an animal model, we saw all these dendritic spines form on the neurons," said, Zylka, who is also a member of the Carolina Institute for Developmental Disabilities. "We thought this was a big deal because too many dendritic spines have been linked to autism."

Their findings thus pointed to hyperactivation of UBE3A as the likely cause of this child's autism.

link.

It is probably not the SOLE cause though.