Autism's DNA trail: gene variant tied to developmental disorder.

Scientists have taken a promising step forward in untangling the genetic roots of autism. Inheritance of a common variant of a gene that influences immunity, gastrointestinal repair, and brain growth substantially raises the chances of developing autism, at least in families with more than one child diagnosed with the severe brain disorder, a study finds.

Children with autism show severe social difficulties, language problems, and repetitive behaviors. The gene, called MET, regulates production of a protein that influences cell proliferation in various parts of the body.

"This is a moderate-to-high-risk autism-vulnerability gene," reports developmental neurobiologist Pat Levitt of Vanderbilt University in Nashville.

Certain variants of the gene, which contain minor alterations in their genetic code, cause several cancers.

Levitt's group had explored how MET contributes to brain development. After learning that the gene lies on a stretch of chromosome 7 that other investigators had linked to autism, the group began its new study.

Consulting a large database, the researchers obtained genetic information from members of 204 families in which one or more children had autism. These children ranged from below average to average in intelligence.

The researchers then identified variants of MET. Study participants who carried two copies of a specific MET variant displayed autism substantially more often than the others did. Levitt's group later found the same association for children with autism in 539 additional families.

Further analyses indicated that the link between the MET variant and autism appeared primarily in families with two or more affected children, the researchers report online this week for an upcoming Proceedings of the National Academy of Sciences.

Laboratory tests showed that this MET form lowers the gene's activity and reduces its production of proteins that bind to various tissues.

If confirmed by other groups, these results would explain controversial reports that people with autism often have immune and gastrointestinal problems, according to Levitt.

Roughly 47 percent of the population carries at least one copy of the autism-associated MET variant. The researchers have yet to learn how it operates in the minority of that group that develops autism, which affects about 1 in 500 individuals, Levitt notes. In some people, beginning before birth, MET might respond to unknown environmental influences or interact with other genes to derail brain formation, Levitt theorizes.

Other researchers had reported preliminary associations between DNA regions and autism. "This is the first time someone has identified a candidate gene for autism, replicated their finding, and demonstrated that gene's biological function," remarks geneticist Daniel H. Geschwind of the University of California, Los Angeles. MET may contribute to autism in diverse ways, he proposes.

However, MET could be just the tip of the genetic iceberg. "Autism will turn out to be many different disorders influenced by hundreds of genes," Geschwind predicts.

An effort is now under way, led by geneticist Anthony P. Monaco of the University of Oxford in England, to gather DNA from as many as 2,000 families with autistic children. When that database is completed in about a year, researchers will use it to confirm whether numerous candidate genes, including the MET variant, contribute to autism, Monaco says.