A Piece of the Puzzle: 8 Autism-Related Mutations in 1 Gene

September 21, 2017

LOS ANGELES -- September 21, 2017 -- Researchers have identified a hotspot for autism-related mutations in a single gene. The findings were published in the journal Nature Communications.

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

The researchers found 8 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 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, University of Southern California College of Letters, Arts and Sciences, Los Angeles, California. “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.”

“Many genes have been implicated in autism,” he said. “What we want to know is: What do these genes have in common? We are looking for the points of convergence that ultimately lead to this spectrum of disorders.”

The researchers 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.

The team found 8 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 Vsevolod Seva Katritch, University of Southern California.

Previous studies have identified a variety of types of problems with brain cell connections that are linked to autism. In some cases, the connections between brain cells appear weaker than normal. In other cases, they seem too strong.

“Most of the mutations we have found in TRIO weaken the protein and result in weaker connections between brain cells,” said Herring. “However, one mutation found in an individual with severe intellectual disability surprised us. It causes TRIO to become much stronger. When this mutant form of TRIO was put into brain cells, it caused them to have way too many connections.”

“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,” he added. “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,” said Herring.

The researchers hope that these new discoveries will be useful in developing new, more effective strategies for treating autism spectrum disorders.

Reference: http://dx.doi.org/10.1038/s41467-017-00472-0

SOURCE: University of Southern California

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