Gene discoveries for autism

Affecting an estimated 1 in 88 US children, autism spectrum disorder (ASD) is a complicated and diverse group of developmental brain disorders that interfere with language, normal communication, and social interaction.

Unlike some other conditions that are caused by mutations in a single gene, as many as 1,000 genes, as well as various environmental factors, are suspected to contribute to the risk of developing ASD. That’s daunting because before we can develop broadly-applicable treatments, we need to figure out which are the key genes, what brain cells they control, and when they are active.

by Francis S Collins, MD, PhD, director of the National Institutes of Health

little-boy-snowy-window(December 3, 2013) NIH-funded researchers at the University of California, San Francisco, Yale School of Medicine, Carnegie Mellon University, and the University of Pittsburgh have taken a significant step in that direction.

When they sifted through protein-coding part of the genetic blueprints of more than 1000 families that had one child with ASD, the researchers discovered among the children with ASD, 144 rare, non-inherited mutations that deactivated various genes. Of these, nine genes harbored several different mutations, suggesting they had the strongest causal links to ASD.

Because the nine genes didn’t fall into a single category, and it wasn’t clear what connected them all, the researchers turned to a digital atlas called BrainSpan. Created by an NIH-supported consortium a couple of years ago, BrainSpan is a valuable resource for all neuroscientists, because it catalogs gene activity in 16 regions of the brain during 15 stages of human development — from embryos to the elderly.

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To the researchers’ surprise, their BrainSpan search showed that in healthy brains, the nine genes implicated in ASD produce proteins that act together during one specific period of time in one certain type of cell in one particular region of the brain.

Specifically, this network of genes is active during early and mid-fetal development (10–24 weeks) in glutamate-producing projection neurons in the prefrontal and primary motor-somatosensory cortex — an area of the brain critical for personality expression, social behavior, and language.

These findings suggest that when any of these nine genes are misspelled, the consequence is disrupted development of the cortical projection neurons, which function rather like interstate highways connecting the two halves of the cortex and linking the cortex to other key areas of the brain.

At the same time, using a different approach, another NIH-funded team at the University of California, Los Angeles, recently found that networks of ASD genes were active in the cortical projection neurons during early development. Taken together, these studies underscore the importance of this cell type and brain region in ASD.

It must be emphasized that the new gene discoveries point to just one of what is likely to be many possible routes to increased risk of ASD. Only about 15% of children with ASD have been found to have non-inherited mutations in these genes, and the remaining 85% must have other causes.

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Still, this work is exciting because it helps to clarify the biological mechanisms underlying ASD, provides a more uniform picture of the mechanism, and gives all who are working to develop treatments and cures yet another important piece in what’s almost certain to be a very challenging puzzle.

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