Eight autism-related mutations in one gene

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By studying data from thousands of genomes of people with autism-spectrum disorders, an interdisciplinary team of USC researchers homed in on a gene called TRIO. The TRIO gene produces a protein that influences the development and strength -- or weakness -- of the connections between brain cells.

The scientists found eight autism-associated mutations clustered within a small region of the Trio protein. Changes in the protein's function early in a child's brain development can, like a wayward driver on a freeway, set off a chain reaction that hampers connections between brain cells and, consequently, hinder the brain's ability to store and process information.

"I have never seen this number of autism-related mutations in such a small area," said Bruce Herring, the study's corresponding author and a neurobiologist at the USC Dornsife College of Letters, Arts and Sciences. "The likelihood that this number of mutations occurs by chance is 1 in 1.8 trillion. We're pretty confident these mutations contribute to the development of autism-related disorders."

this study, Herring and his team studied the genomes of 4,890 people with autism-related disorders. Sifting through the data, they hunted for genetic mutations that may have a significant role in the development of autism.

"TRIO ended up very high on our list," Herring said.

The team found eight mutations associated with autism in a small area of the TRIO gene -- the GEF1/DH1 domain. This domain encodes a specific area of the Trio protein that turns on another protein, Rac1, that builds the scaffolding for the brain's connections.

In a normal brain, the GEF1/DH1 domain binds to and activates Rac1, prompting the growth of actin filaments that form the scaffolding.

Most of the autism-related mutations discovered in this study prevent the Trio protein's ability to activate Rac1. The interference causes the scaffolds to break down, weakening the brain's connections. As a result, the brain cells have trouble communicating with each other.

"It is really striking that all disruptive mutations are found in the positions where they either weaken the domain structure or block its interactions with Rac1, a key hub for the neural development pathways," said study co-author Vsevolod Seva Katritch, an assistant professor for biological sciences at the USC Michelson Center for Convergent Bioscience and USC Dornsife

"I don't think it really matters if connections between brain cells are too strong or too weak. I think either case can contribute to the development of autism," Herring said. "The ability of our brains to increase and decrease the strength of connections between brain cells is essential for normal brain development; our brains must be plastic. Mutations that push connections too far in either direction are likely to impede our brain's ability to change in appropriate ways."

"We believe autism-spectrum disorders are likely to develop from mutations that take away the brain's ability to change during a critical time point in a child's brain development, when the brain cells are trying to establish the appropriate connections and build the right circuits," Herring said.