Even though previous studies on autism had implicated over a thousand different genes, their exact role in the onset of the disease has been unknown. Now, a group of researchers from the University of North Carolina (UNC) School of Medicine in Chapel Hill, has pinpointed the mechanism behind one of these genes, called UBE3A.
“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 Mark Zylka, Associate Professor of Cell Biology and Physiology at UNC, and senior author of the new Cell paper.
In individuals with autism, duplication of the 15q chromosome region – referred to as Dup15q Syndrome – is one of the most common genetic abnormalities. The question is – what causes it?
To figure that out, Professor Zylka and his team sequenced the genes of human cell lines from children with autism and their parents.
What they found was that, in people with autism, the UBE3A gene, which can be turned on or off via the attachment of a phosphate molecule in healthy individuals, becomes overactive and eventually leads to the development of pathology.
The regulatory “switch” – identified as Protein Kinase A (or PKA) – is missing in autistic children, but not in their parents.
To make their findings even more robust, Zylka and his colleagues introduced the mutated gene into a number of mouse models, revealing an overdevelopment of dendritic spines (small membranous protrusions that connect neurons to synapses), which has been linked to autism in work done by other researchers.
The new discovery, rather than being a pronouncement of genetic “doom”, might actually lead to new treatments that focus on decreasing the activity of UBE3A. In fact, the team had already tested a few compounds, successfully demonstrating their efficacy at increasing the activity of PKA, which, in turn, leads to the “quieting” of the defective gene.
In addition to opening the doors to potential autism treatments, the researchers claim their findings may also help people with Angelman Syndrome – a rare neurological disorder that causes severe intellectual and physical disability.
Zylka’s team has found that people with the syndrome have an unstable and largely-inert version of UBE3A, responsible for certain mutations that lead up to the development of this debilitating disorder. The new findings could help increase the accuracy of tests used for diagnosing the syndrome, which currently lead to many cases of misdiagnosis.
The study was published in the science journal Cell.