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John Hopkins-led team finds key genetic player in autism: semaphorin 5A
10-12-2009
by Jeffrey Bouley  |  Email the author
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BALTIMORE—Despite the fact that genetic causes are suspected in 90 percent of the disorders that are on the autism spectrum, identifying the responsible genes has proven tricky. However, an international group of researchers, led by a team at Johns Hopkins University, has added considerably to the genomic information in this area by identifying several genetic links to autism, chief among them a variant of semaphorin 5A, whose protein product controls nerve connections in the brain. 
 
Publishing in early October in Nature, the researchers note that semaphorin 5A was already been known to play a role in guiding neurons to the right connecting points in the brain during fetal development. In addition, the team reported additional evidence that many rare and common genetic variants contribute to autism.
 
It is tempting, of course, with a breakthrough like this, for people outside of the research community to get ahead of themselves and see possibilities for predictive or diagnostic tests, or for treatments in the near term, notes Dr. Aravinda Chakravarti, professor of medicine, pediatrics, and molecular biology and genetics at the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins. But this is just an important early step in understanding autism, he adds.  
 
"As a society, we've gotten to the point where we want the 'instant coffee'—one of the worst inventions that human creativity has ever produced," Chakravarti says. "But we cannot have good therapy, or diagnostics, or anything else like that, without understanding what it is that we are targeting and why. We really don't know a lot of details right now, but it seems clear we're on a promising track, and I have no problem being patient and finding out more about something we don't know much about, and wait on the diagnostics or therapies much farther down the line."  
 
In fact, it isn't at all clear that semaphorin 5A or any of the other genes being investigated would even be good diagnostic or therapeutic targets; only that they are key players apparently, Chakravarti says.  
 
He likened the current research findings to baseball, though he jokes that he hates making a sports analogy out of it, saying, "We're not at the World Series yet with this. Maybe we've just hit a home run in the sixth inning of the tenth game in the regular season. That's important, but it's not the end of the journey, and many people will build off what we've done and go off in their own directions as well."
 
In the current work, the researchers verified that semaphorin 5A plays a role in autism by looking at brain tissue samples from the Autism Tissue Program and the Harvard Brain Bank. In doing so, they found that the amount of the semaphorin 5A protein was significantly reduced in the brains of those people with autism compared to brains of the non-autistic.  
 
This suggests that autism may occur due to differences in how nervous system connections are made in the brain, the researchers note.
 
The identification of semaphorin 5A, and seven additional likely—but not yet proven—genes involved in nervous system development, cell structure and other cell functions, was possible only because of an "extensive collaborative effort that included inpatient samples from the Autism Consortium in Montreal, the Autism Genome Project and additional samples from Finland and Iran," the Johns Hopkins team reported when it announced the findings.
 
"The biggest challenge to finding the genes that contribute to autism is having a large and well-studied group of patients and their family members both for primary discovery of genes and to test and verify the discovery candidates," Chakravarti notes. "This latest finding would not have been possible without these many research groups and consortia pooling together their patient resources. Of course, they would not have been possible without the genomic scanning technologies either."  
 
Using such genome-wide scanning technologies, the team examined the genomes of family members, among whom more than one individual was diagnosed with an autism spectrum disorder. They studied 1,031 nuclear families in total, and 1,553 affected children, looking at 500,000 single nucleotide polymorphisms for differences that stood out in the DNA. The information was collected from two sources: the Autism Genetic Resource Exchange and the U.S.-based National Institute of Mental Health.
 
They performed two types of genetic analyses to identify genes with both rare and common genetic variations that might contribute to autism. By studying siblings with autism, the authors discovered four regions of the human genome—on chromosomes 6, 15, 17 and 20—where rare variants in yet unidentified genes appear to contribute to autism susceptibility. After examining the genetic patterns in unrelated people with autism, the researchers discovered a common variation near only one gene, and that was semaphorin 5A.  
 
The fact that only one common variant came out of this large sample study indicates that "there probably are many more that contribute to autism, but none have large effects," says Dr. Dan Arking, assistant professor of medicine at Hopkins' McKusick-Nathans Institute of Genetic Medicine. "Alternatively, there may be numerous rare gene-variant containing genes."  
 
Identifying these will require even larger collaborative studies, some of which are already in progress, he adds.
 
Next steps in the research will be to continue to pool current and future data with that of other groups with similar genome-wide work, not just with semaphorin 5A but also with the other four genes the Johns Hopkins-led team discovered, and others that may be uncovered later by them or someone else.  
 
"These discoveries are an important step forward, but just one of many that are needed to fully dissect the complex genetics of this disorder," says Dr. Mark Daly, a senior associate member at the Broad Institute of Harvard and MIT and an associate professor at the Center for Human Genetic Research at Massachusetts General Hospital. "The genomic regions we've identified help shed additional light on the biology of autism and point to areas that should be prioritized for further study."  
 
The research at Johns Hopkins University was supported by the National Institutes of Mental Health and the Simons Foundation.
 
Code: E10140904

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