Autism spectrum disorders share common molecular causes

Neurodevelopmental disorders such as intellectual disability and autism spectrum disorders can have profound, lifelong effects on learning and memory, but relatively little is known about precise molecular pathways that cause these diseases.

Now, a team of McGill University researchers led by psychiatry professor Carl Ernst has discovered that autism spectrum disorders caused by distinct genetic mutations have similar molecular effects on cells -- suggesting that similar therapeutic approaches could be effective for conditions ranging from seizures to intellectual disability. The study will be published in the November issue of American Journal of Human Genetics.

“Autism spectrum disorders associated with a specific genetic mutation are rare, and as a result, developing therapeutic intervention options is not efficient,” says Prof. Ernst, who is also a researcher at the Douglas Hospital Research Institute. “There are a lot of genes that have been associated with autism spectrum disorders. Once we fully define the major common pathways involved, targeting these pathways for treatment becomes a viable option that can affect the largest number of people.”

Modeling autism in genetically engineered human stem cell models

To see if different types of autism spectrum disorders converge, Ernst and his team modeled two genetic syndromes associated with autism in human fetal brain cells. They modeled mutations in transcription factor 4 (TCF4) that cause Pitt-Hopkins syndrome , characterized by intellectual disability and psychiatric problems, and mutations in euchromatic histone methyltransferase 1 (EHMT1), which cause Kleefstra syndrome.  About 60% of the clinical profile from these two syndromes overlaps, including behavioral problems, intellectual disability, and facial anomalies.  Ernst and his team found that several features of neural stem cells were similar in the two disease models. DNA methylation, a chemical tag important in cell function, showed similar patterning, as did microRNA – small particles that can drive many important effects, from cell death to differentiation. Cells in both modeled disease states also shared characteristics of normal cells that were more mature, suggesting that a main underlying mechanism of ASDs may be a reduced ability for cells to decide the appropriate time to specialize. Cell specialization in the human brain is fundamental to appropriate brain development and behaviour.

“Our study suggests that one fundamental cause of disease is that neural stem cells choose to become more mature brain cells too early,” Ernst says. “This could affect how they incorporate into cellular networks, for example, leading to the clinical symptoms that we can see in kids with these diseases.”

In the future, Ernst and his team hope to assess whether modeling other genes known to be associated with autism shows similar molecular convergence to the two genes studied here.  “I’d really like to see if the regulation and timing of neural stem cell maturation is an underlying feature across autism and other neurodevelopmental disorders,” Ernst says.

This research was supported by the Scottish Rite Charitable Foundation, the Banting Foundation of Toronto, and the Canada Research Chairs program.

The first authors of the study were part of the McGill-Brazil scholars program (https://www.mcgill.ca/ipn/prospective/brazil). 
 
Molecular Convergence of Neurodevelopmental Disorders by Carl Ernst et al will be published in the American Journal of Human Genetics on October 9 at noon.http://www.cell.com/ajhg/abstract/S0002-9297(14)00396-6