RNA discovery offers clue in autism puzzle

Scientists have discovered the first gene associated with autism that has genome-wide significance—findings that could lead to new treatments. The discovery, detailed in the journal Science Translational Medicine, may allow researchers to study the causes of autism and develop new treatments for the disorder more effectively. “Our study shows that a highly-significant genetic signal for autism pointed to a new gene, MSNP1AS,” says Daniel B. Campbell, the study’s senior author and assistant professor of psychiatry and the behavioral sciences at University of Southern California‘s Keck School of Medicine. “MSNP1AS is a non-coding RNA, which means it does not code for a protein. More than half of the RNAs made in the human brain are non-coding, but their functions are often unknown. We found that expression of MSNP1AS is increased 12-fold in the brains of people with autism and discovered that it controls expression of a protein called moesin, which influences brain development and immune response. “The discovery of a functional non-coding RNA opens new avenues of investigation for autism.” Autism spectrum disorder (ASD) is a lifelong neurodevelopmental disability characterized by problems with social interaction, communication, and repetitive behaviors. The Centers for Disease Control and Prevention estimates that 1 in 88 children in the United States have an ASD. ASD is highly heritable, suggesting that genetics are an important contributing factor, but many questions about its causes remain. There currently is no cure for the disorder. A 2009 study published in Nature by Kai Wang, now assistant professor of psychiatry and preventive medicine at the Keck School, found a significant association of genetic risk factors underlying ASD with genetic markers on chromosome 5. The nearest genes (CDH9 and CDH10), however, were more than 1 million base pairs from the marker—too far to explain the link to autism. Campbell and his team at the Keck School’s Zilkha Neurogenetic Institute hypothesized that a previously undetected genetic component might lie closer to the markers. Using bioinformatics techniques, they discovered that a new gene, MSNP1AS, was located directly at the autism-associated genetic markers. They also found that expression levels of the gene were higher in brain samples from autism patients than in samples from healthy individuals. Finally, they showed that over-expression of MSNP1AS caused a decrease in moesin protein. “The autism genetic signal gave us a treasure map with a big X over the Mojave Desert,” Campbell says. “Instead of searching in the bright lights of Las Vegas or Los Angeles, the nearest big cities, we decided to search right under the big X on the map. We discovered the treasure (MSNP1AS) in the desert, just where the map said it was. “And, once we found the treasure, we realized that it was a key to a mansion in Paris—that MSNP1AS regulates expression of moesin, a protein that is generated by a gene on the X chromosome (a different continent) and is known to impact both brain development and immune response.” Previous studies had shown that moesin RNA was central to a network of genes with altered expression in post-mortem brain samples from people with autism. Like the previous studies, Campbell and colleagues found that moesin RNA levels were increased in those brain samples, while actual moesin protein levels were not. “This suggests that MSNP1AS RNA may play a role in suppressing moesin protein expression, which may increase the risk for autism,” says Tara Kerin, the study’s lead author and a Ph.D. candidate in preventive medicine. While their results hint that both MSNP1AS and moesin could potentially be targets for therapy, there is simply too much information that remains a mystery. “This is just a first step,” Kerin says. “It’s just another clue that may help unlock the puzzle that we have before us.” Other USC co-authors include Anita Ramanathan, Kasey Rivas, Nicole Grepo, and Gerhard A. Coetzee.