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Researchers show how specific gene change causes subtype of autism

Discovery suggests that known drug may help people affected by a severely disabling form of autism; but safety testing needed
August 06, 2015

University of North Carolina researchers have worked out how changes to a specific autism-related gene cause a severely disabling form of autism – with clear implications for treatment.

Their findings appear today in the journal Cell.

Autism Speaks helped support the work with a research grant. Additional funding came from the National Institutes of Health, the Angelman Syndrome Foundation and the Foundation for Angelman Syndrome Therapeutics.

In today’s report, brain biologist Mark Zylka and colleagues show that a specific autism-linked gene change interferes with an important enzyme, or chemical “switch,” in the brain. This enzyme, dubbed UBE3A, switches off and on with the addition and removal of a phosphate molecule. Precise control of its activity is crucial for healthy brain development and normal brain function.

The gene mutation destroys the ability of the phosphate molecule to turn off the switch. As a result, UBE3A becomes hyperactive and drives abnormal brain development and autism. The work was done in human cell lines, as well as mouse models.


A new direction for treatment

Importantly, the researchers also identified the protein that tacks the phosphate group onto UBE3A. It’s protein kinase A, or PKA. The finding has treatment implications because a number of existing drugs can raise or lower PKA levels in the body.

Such medicines may hold particular promise for treating Dup15q syndrome. The disorder involves duplication of chromosome 15 and affects around 5 percent of people who have autism. It’s also commonly associated with severe physical and intellectual disabilities and seizures.

“We think it may be possible to tamp down UBE3A in Dup15q patients to restore normal levels of enzyme activity in the brain,” Dr. Zylka says. “In fact, we tested known compounds and showed that two of them substantially reduced UBE3A activity in neurons.”

One of the drugs, rolipram, had been previously tested to treat depression but was discontinued due to side effects. The researchers propose that it may be worthwhile to try lower doses in light of the fact that Dup15q is also associated with life-threatening seizures. “The benefits might outweigh the risks,” Dr. Zylka says.

First the team plans to test this approach with mice genetically engineered to have the Dup15q gene mutation.

In addition, the team identified other gene mutations that disrupt the brain’s UBE3A switch in Angelman syndrome, which likewise involves a severely debilitating form of autism. The Angelman’s mutations essentially eliminate UBE3A. This raises the possibility of future treatments that increase or restore the enzyme.

“The identification of genetically defined subpopulations is an important first step in developing targeted and effective new therapies,” comments geneticist Mathew Pletcher, Autism Speaks vice president for genomic discovery. 

This type of result – using genetic discoveries to advance research on personalized treatments – is the goal of Autism Speaks MSSNG program. MSSNG is harnessing the information in 10,000 whole genome sequences from families affected by autism to provide meaningful information for researchers, healthcare providers and people with autism.


MSSNG: “What we know about autism is not enough; MSSNG is the search for the answers.”