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Research on Girls Provides Insights into Severe Autism

Autism Speaks Weatherstone fellow uses novel approach to uncover genes associated with severe autism
March 25, 2015

By focusing on girls severely affected by autism, researchers have identified a new gene strongly associated with autism and shed new light on the disorder’s root causes.

The study appears online ahead of the April 2 issue of the journal Nature.

Autism Speaks co-funded the research through a Weatherstone Predoctoral Fellowship for lead author Tychele Turner, at Johns Hopkins University.

Learn more about Autism Speaks Weatherstone Predoctoral Fellowships here.

Turner focused her genetic research on girls, she explains, because a growing body of research suggests that they are partially protected against autism. Girls and women make up just 20 percent of those affected by autism. But when they do develop the disorder, their symptoms tend to be more severe. Consequently, researchers have proposed that it takes a stronger genetic “hit” to tip the developing female brain into autism.

Following this line of thinking, Turner and her colleagues identified 13 families with more than one female affected by autism. In doing so, they associated autism with four genes not previously linked to the disorder.

They then delved deeply into one gene, CTNND2, to better understand its role in brain development. Their studies included analysis of the gene’s activity in the developing brains of zebra fish, mice and post-mortem human brain tissue.

They found that CTNND2 produced a protein (delta-catenin) found at high levels in the brain before birth. So it likely plays a key role in early brain development. Specifically, mutations in CTNND2 disrupted the connections called synapses that form between brain cells. This bolsters earlier evidence that problems with brain connectivity are the root cause of autism.

In addition, the research team found many interactions between CTNND2 and other genes involved in brain development. (See illustration below.)

"These findings are important on two levels,” comments Paul Wang, Autism Speaks head of medical research. “They help confirm that autism involves problems in connectivity between neurons during early brain development. The study also gives us a wealth of information about a particular gene that may offer new targets for medical treatment of severe autism.”

Turner and her colleagues are now working to find the functions of the other three genes that their analysis associated with severe autism.

Her co-authors included Kamal Sharma, Maria X. Sosa, Dallas R. Auer, Vasyl Pihur, Richard Huganir, and Aravinda Chakravarti of The Johns Hopkins University; Edwin C. Oh, Yangfan P. Liu, Nicholas Katsanis of Duke University; Ryan L. Collins, Harrison Brand and Michael E. Talkowski of Massachusetts General Hospital and Harvard Medical School; Stephan J. Sanders and Matthew W. State of the University of California, San Francisco, Daniel Moreno-De-Luca of Yale University; Christa Lese Martin of Geisinger Health System; Teri Plona, Kristen Pike, and Daniel R. Soppet of Leidos Biomedical Research; Michael W. Smith of the National Human Genome Research Institute; SauWai Cheung of Baylor College of Medicine; and Edwin Cook of the University of Illinois at Chicago.

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