Mutations of Autism

Mutations of Autism

UNC Researchers Discover Specific Mutation that Causes Autism Spectrum Disorder
August 27, 2015 


Scientists from UNC School of Medicine have discovered how a specific mutation can cause autism spectrum disorder.

Mark Zylka, a cell biology and physiology professor at the UNC Neuroscience Center, showed that a mutation to a single enzyme can cause structural changes to the whole brain, and thereby cause autism.

The Centers for Disease Control and Prevention estimates that one in every 68 children is diagnosed with autism spectrum disorder, a class of disabilities that may hamper the development of social and behavioral skills.

Scientists have previously identified mutations in more than 100 genes related to autism spectrum disorder and hypothesize there may be as many as 1000. Zylka and his team, however, are the first to identify exactly how, on a molecular level, one of these genes can cause autism.

It begins with an enzyme called UBE3A. While the exact function of UBE3A in the brain is unknown, it belongs to a family of enzymes called ubiquitin protein ligases, whose job it is to mark old and nonfunctional proteins for recycling.

The body needs these sorts of enzyme garbage men to keep cells clean and efficient, but left to run wild the ubiquitin protein ligases will start making jobs for itself to do, and good proteins start getting marked for degradation.

As such, the body keeps enzymes like UBE3A “on retainer.” In its normal state, UBE3A will work and work and work, so the body has another enzyme called protein kinase-A (PKA) give it a phosphate ion. Phosphate is a very common currency in the enzyme world and the exchange of phosphates causes all sorts of enzymes to do (or stop doing) all sorts of jobs.

PKA is like the cellular payroll department. It will encounter UBE3A after its work is done, give it a phosphate ion for its trouble, and the UBE3A is content to hang out until it is needed again — when the phosphate is removed.

Zylka found that a mutation common in children with autism spectrum disorder slightly warps the segment of UBE3A that would receive the phosphate. So UBE3A just keeps working away, and no matter how hard PKA tries, it can’t give UBE3A its phosphate.

In animal models, Zylka saw that hyperactive UBE3A leads to an abnormally large number of what are called dendritic spines growing on brain cells. Dendritic spines are like tiny satellite dishes that receive information from other nerve cells. In this case, you can have too much of a good thing as many brain disorders, including autism, are linked to an excess of dendritic spines.

The fact that autistic children showed heightened UBE3A activity while their parents, who did not have autism spectrum disorder, did not was Zylka’s smoking gun.

Now that we know how this particular mutation works, the question becomes “what can we do about it?” Zylka says there is both good and bad news on that front.

The good news is there are drugs now that can increase the effectiveness of PKA. Zylka experimented with these compounds and showed that two of them were effective in shutting down UBE3A. According to Zylka, there are several other mutations on nearby genes or clusters of genes that would also cause a hyperactive UBE3A, which means that these drugs could treat not just one autism-related mutation, but several common ones.

The bad news is those drugs need some refinement. One of them was pulled from a clinical trial (for depression) because it caused seizures in high doses. Zylka says that smaller doses of the drug might be useful in providing some symptom relief, but more studies are needed to see whether that can be effective.

Either way, this study represents a step forward in our understanding of autism spectrum disorder, and while it covers only one mutation of many, future studies may provide similar insights into other mutations. Zylka’s study appeared in the journal Cell.

— Daniel Lane

Daniel Lane covers science, engineering, medicine and the environment in North Carolina.