Forward Genetics Technique Used to Identify Autism Gene

Researchers at UT Southwestern have adapted forward genetics to identify new genes involved in autism spectrum disorder (ASD). In a study published in eLife, the team used this approach in mice and identified a gene called KDM5A.

"The difficult part in the beginning was finding the mutations. It had to be done by laborious cloning," says Bruce Beutler, co-author of the study. "We developed a platform wherein when you see a phenotype you know the mutational cause at the same time." This technique, combined with a screen developed to ascertain ASD-like behaviors in mice, made it possible to use forward genetics for the first time to identify new genetic mutations in ASD.

In this study, the research team documented the quality and number of vocalizations in young mice carrying induced genetic mutations. Given that one of the common characteristics seen in autism is disrupted communication, the researchers were on the lookout for mice that had changes in these vocalizations.

In addition to loss of vocalizations, mice lacking KDM5A also displayed repetitive behaviors and deficits in social interaction, learning, and memory—all hallmarks of ASD. Because this was the first time that KDM5A had been implicated in ASD, the researchers looked into whether KDM5A mutations could be found in patients with autism as well. Through international collaborative efforts, the group was able to identify nine patients with ASD and causative KDM5A mutations. Strikingly, eight out of nine patients also had a complete lack of speech.

Aside from the impact on diagnosis, the researchers are interested in further characterizing this gene's role in the brain. With a better understanding of what KDM5A is doing in the brain, the scientists are hopeful that they might be able to find a target to aid in future studies investigating possible treatments.