Reporting in the current issue of the Proceedings of National Academy of Science, an international team of scientists led by Pat Levitt, Ph.D., chair of the Cure Autism Now Scientific Advisory Board, has identified a functional genetic variant significantly associated with autism, which appears to double the risk for autism and may explain some of the ancillary symptoms associated with the disorder. The group of scientists examined a gene called MET tyrosine kinase and found a strong
association between autism and a variant of the gene that appears to result in a decreased production of the protein it encodes.
Dr. Levitt, director of the Vanderbilt Kennedy Center and a developmental neurobiologist, and Dr. Daniel Campbell, a research associate in his laboratory, have spent the last several years studying the role of the MET gene in brain development. The team had previously reported that mice having reduced levels of the gene had anatomical abnormalities in the cerebellum and cerebral cortex, and suffered from intermittent seizures. Behaviorally, the mice showed signs of increased anxiety as well as deficits in social interactions. As all of these features are reminiscent of the pathophysiology of autism, Dr. Levitt suspected that MET may somehow be involved in autism. Moreover, the MET gene is located on chromosome 7 in a genetic region previously linked to autism. Yet, to Dr. Levitt's astonishment, MET had never been studied as a potential candidate gene underlying autism susceptibility.
“From our previous studies, MET seemed like a great biological candidate for involvement in autism,” explains Dr. Levitt. “What was intriguing to us was the fact that the MET signaling protein, made by the MET gene, is known to participate in immune system regulation and gastrointestinal repair as well, so we found it interesting that a significant number of children with autism have reported symptoms related to chronic gut and bladder control and frequent infections and allergies. We recognized that it was a bit unusual to think about a gene that participates in several important biological processes, rather than just brain development. We also realized that many geneticists probably skipped over doing detailed analysis of the gene because MET actually is implicated in certain types of cancer as well.”
In an initial screen the research team examined the association of autism and the MET gene in 243 families by looking at how often specific variants of the gene were passed through the generations from parents to their affected children. In theory, there should be no bias in which form of the MET gene gets passed down from parents to their children. However, if a particular form gets passed to affected individuals significantly more often than another, an association is thought to be present. In this way, a significant association was found between one specific form of the MET gene and autism. The researchers were then able to confirm these findings using 500 families from the Cure Autism Now Autism Genetic Resource Exchange (AGRE) collection, determining that the association especially holds true in families with more than one affected child. Their analyses revealed that individuals with two copies of this specific MET gene variant ultimately have more than a two-fold increased likelihood of developing autism.
Having identified the association with a particular DNA change in the MET gene, the research group was interested in finding out if the DNA change had any functional consequence. The DNA change was located in a region typically involved in the regulation of gene expression, called the “promoter” region, which controls the amount of the gene that is produced and turned into protein. The research team was able to determine that the gene variant associated with autism resulted in the production of less than half the amount of MET protein. Thus, the DNA change influences how much of the MET gene is made, suggesting that individuals who inherit the autism-associated form of the MET gene may ultimately have less MET protein signaling. Finally, it is known that certain types of “regulatory” proteins can stick to the promoter part of the gene to turn the gene “on” or “off”. Dr. Levitt's team went on to demonstrate that the decreased MET gene expression is due to a reduction in the ability of the regulatory proteins to bind to the promoter of the autism-associated variant and turn it “on”.
Although other candidate genes have been associated with autism, the vulnerability imparted by the gene variant described by Dr. Levitt's team is greater than that of any of the other genes so far associated with autism. It is also one of the first to have an obvious functional consequence, which can now be studied in detail to understand its biological impact. However, as Dr. Levitt notes, “This is a very common genetic variant. Approximately 47% of the population carries it, which means that inheriting this particular form of the MET gene does not in itself cause autism. We are now in a position to identify further risk factors, genetic or environmental, that cooperate with MET to trigger autism. For example, we would like to know whether carrying the ‘at-risk' form of the MET gene makes one more susceptible to certain kinds of environmental factors that may be part of the trigger for autism. Because we know that autism is a highly inherited disorder, doing studies on environmental factors without considering genetic risk is less likely to yield the kind of critical information that might help get us closer to causes of autism.”
In this elegant set of experiments, Dr. Levitt and his colleagues have demonstrated that a specific DNA change in the MET gene acts as a heritable risk factor that contributes to autism susceptibility. Although having this specific form of MET is not diagnostic nor predictive, it may help screen for individuals at-risk for developing autism, especially in families in which there are already affected individuals. Most importantly, identifying a specific gene, especially a functional variant of that gene, provides clues to the critical cellular pathways that may be involved in causing autism, but have so far been difficult to uncover. For those already afflicted, an understanding of the affected biology will allow us to design treatments that can compensate for the disrupted biochemical pathways, such as those that could be involved with MET protein signaling. The MET gene will now be placed into models of how autism may develop, given both the alterations in brain development and the ancillary symptoms in some children with autism, such as potential digestive system sensitivities and hyperimmune status. Future analyses will focus on other candidate genes that are involved in MET function and that are also located at chromosomal “hot spots” for autism, the construction of a mouse model to more accurately determine the biological effects of carrying this specific MET variant, and identification of further risk factors that synergize with its inheritance.
Dr. Levitt has served as the Chair of the Cure Autism Now Scientific Advisory Board for the past four years, and has been a strong supporter of Cure Autism Now for many more. Cure Autism Now wishes to publicly congratulate Dr. Levitt on his research, as well as on his recent appointment by the U.S. Department of Health and Human Services to the National Advisory Mental Health Council. The work described in this article was supported by the National Institute of Mental Health, National Institute of Child Health and Human Development, the Marino Autism Institute, Telethon-Italy, Cure Autism Now (Dr. Persico only), National Alliance for Autism Research, The Foundation Jerome Lejeune, and National Alliance for Research on Schizophrenia and Depression.