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Researchers Discover Potential Cause of Autism in Key Enzyme Group

Study sheds light on possible environmental factors behind autism spectrum disorders
August 28, 2013

When a key group of enzymes called topoisomerases are impaired or inhibited, it can have a profound impact on the function of many genes important for development and potentially lead to autism spectrum disorders (ASD), according to a new study published Wednesday in the journal Nature.               

“Our study shows the magnitude of what can happen if topoisomerases are impaired,” said senior study author Mark Zylka, associate professor in the Neuroscience Center and the Department of Cell Biology and Physiology at the University of North Carolina School of Medicine.  “Inhibiting these enzymes has the potential to profoundly affect neurodevelopment – perhaps even more so than having a mutation in any one of the genes that have been linked to autism.”

The main function of topiosomerases, enzymes found in all human cells, is to untangle DNA when it becomes overwound, a common occurrence that can interfere with key biological processes. Zylka’s team stumbled upon their discovery by accident while studying topotecan, a topoisomerase-inhibiting drug that is used in chemotherapy.  While investigating the drug’s effects in mouse and human-derived nerve cells, they noticed that the drug tended to interfere with the proper functioning of genes that were exceptionally long and composed of many DNA base pairs. The researchers then made the serendipitous connection that many autism-linked genes are extremely long. “That’s when we had the ‘Eureka moment,’” said Zylka. “We realized that a lot of the genes that were suppressed were incredibly long autism genes.”

The study could have important implications for ASD detection and prevention and explain why some people with mutations in topoisomerases develop autism and other neurodevelopmental disorders, the researchers said.

Previous studies have shown that topoisomerases are sensitive to the effects of environmental factors. It is not difficult to imagine a scenario where chemicals or compounds in the environment could disrupt the functions of these proteins, leading to enhanced autism risk, and offering the research community a novel opportunity to explore gene-environment interactions in autism. 

Andy Shih, Ph.D., senior vice president, scientific affairs, for Autism Speaks commented on the study for