Mark Zylka, University of North Carolina
Kat - Recent advances in genetics have allowed researchers to start pinning down thousands of gene faults or mutations involved in a wide range of diseases and disorders, from cancer and heart disease to schizophrenia or depression. A gene recently linked to autism encodes a protein called UBE3A, which appears to control how nerve cells in the brain connect to each other. The levels of UBE3A are normally controlled by a kind of molecular switch known as phosphorylation - which involves attaching a chemical tag to a site on UBE3A, switching it off. But what happens when that switch can’t be thrown and UBE3A can’t be turned off? The result is autism, according to University of North Carolina researcher Mark Zylka.
Mark - Basically, as with many things in science, we got lucky. There's really a revolution that’s taking place in the area of autism genetics and this is a revolution that’s really just begun a few years ago. There are several large groups, large consortia, that are sequencing the genomes of individuals with autism and their unaffected parents, and they're searching for genetic mistakes in the kids that are not present in the parents. What they're finding are a large number of these new mutations that are present in the children with autism that are not present in the parents.
Two of these studies were just published in December. In these studies, there are literally thousands and thousands of mutations. One of them was in UBE3A. I sent that information to Jason Yee, a post-doc in my lab and I asked him, “Could you tell me where is this mutation in UBE3A?” A couple of hours later, he basically came back to me. He had this huge grin on his face. He said, “You're not going to believe this, but that mutation is in the phosphorylation site that prevents phosphorylation.” And so, that was really the 'eureka' or the ‘aha’ moment, but as with anything, we wanted to really confirm this.
This material is available so we were able to obtain the cells from the child and the parents, grew them up in our lab and then sequence to confirm that that child did indeed have that mutation whereas the parents did not and then we were able to get UBE3A extracted from those human cells and show that the individual with autism had a hyperactive version of UBE3A whereas the parents did not. And so, that was really unprecedented for us to be able to do something like that.
Kat - We know that autism is a neurodevelopmental disorder. It causes changes, problems in the brain. Were there any signs that having this overactive protein might be affecting any of the cells in the brain?
Mark - We believe, yes. And so, the way we looked at that was to take this hyperactive version of UBE3A and insert it into the brain of an animal model in a subset of cells, a subset of neurons, and then we looked at those neurons that contain this hyperactive version of UBE3A and looked at the number of spines or dendrites on the neurons. Spines make up synapses and synapses are essentially the points of communication from one neuron to the next. What we noticed was that the neurons that took up this hyperactive version of UBE3A had many more spines than the neurons that did not. This again, really points a finger towards autism because of autopsy studies that have been done - one of the hallmark features of individuals with autism is an excess of spines in their brain.
Kat - Potentially, what proportion of cases of autism are we talking about being caused or being involved with this kind of genetic fault?
Mark - It’s about 0.25 per cent of all patients with autism. That may seem like a small number, but this actually represents the third most common chromosomal abnormality in patients with autism. So, it’s a fairly common form of autism.
Kat - I'm sure that people who have children with autism will be thinking, okay, so where are some cures then, where are some treatments? How could this work pave the way for maybe treatments that could help children with autism?
Mark - What this work suggests is that targeting UBE3A, turning off UBE3A might represent a new way to treat autism so we can take advantage of this phosphorylation event that could in turn tamp down the activity of UBE3A and hence, provide a therapeutic benefit.
Kat - It sounds like genetics has really changed our understanding of autism and the way that we research it. How do you see this revolution continuing?
Mark - Just like with cancer, there are many different types of cancer. There clearly are many different genetic types of autism. Sequencing individuals with autism is going to be the future. So, we’re no longer lumping them altogether as individuals with autism but as individuals with certain forms of autism.
Kat - Mark Zylka from the University of North Carolina, and that research was published this week in the journal Cell.