Hunt for Autism Gene Gets Complex
One clue was a region of mouse brains that looked like a cut-and-paste job. Other hints came from methodically trolling through the human genes. And now scientists hope they’ve picked up the scent for identifying genes that set up some babies to develop autism.
Nobody can declare a clear victory yet. A proposed autism gene that captured headlines in November, for example, will have to be confirmed by further research before it’s widely accepted.
But gene hunters say the search has been heating up in the last few years, with more investigators, sophisticated tools and techniques being brought to bear, and a run of tantalizing results.
Once they start finding genes--nobody knows how many might be involved--researchers hope to acquire clues into the roots of the dimly understood disorder.
Autism usually appears by age 3, mostly in boys. Affected children have trouble communicating and interacting with others. They may not respond to their names or even look at other people. In severe cases they may become aggressive or injure themselves.
Scientists hope that finding genes can answer several key questions:
* What exactly goes wrong in the brain to cause autism?
* Are there particular targets for drugs to treat or prevent it, even before birth?
* Do symptoms result from a single event in the brain, or from a process that could be interrupted?
* Could people destined to develop autism be recognized at birth, before symptoms appear, allowing for early intervention?
The hunt for autism genes is complicated. It’s not a case of a single flawed gene causing a disease, as in Huntington’s or cystic fibrosis. Rather, autism appears to be brought on by unknown environmental influences coupled with a dimly understood combination of genes that make people vulnerable.
That’s the case with some other conditions, such as diabetes, heart disease and schizophrenia. And it makes these “susceptibility genes” much harder to find.
When a person inherits a disease-promoting version of such a gene, it only tips the scale toward illness rather than causing it outright; a link between a gene and a disease can be difficult to demonstrate.
But autism also offers an advantage for gene hunters: The genetic effect on susceptibility is strong. The rate of autism in the general population is about two-tenths of a percent or less, but for siblings of an autism patient it jumps to around 3%. And for an identical twin of an autism patient, someone who shares all the patient’s genes, the rate is 60% or more.
That powerful genetic influence lured investigators into the autism gene hunt around the mid-1990s, giving hope for quick success.
“I thought this would be an easy find. I really did,” said Susan Santangelo of the Tufts School of Medicine and Harvard School of Public Health.
As she and others looked for the genes, however, they came to believe that this inherited influence was split among more genes than expected, leaving no gene with an easily traceable influence. That made it harder to find any of them.
If only three or four genes were responsible, “we could have done it,” said neuroscientist Joseph Buxbaum of the Mount Sinai School of Medicine in New York. “We now think our estimates of the number of genes is too low, because we haven’t done it.”
Nowadays the “wild optimism” of the mid-’90s has given way to a more realistic appreciation of the challenge, says Gerard Schellenberg, a research professor of medicine at the University of Washington. But he and some others say it’s possible that autism will be the next common psychiatric disorder, after Alzheimer’s, to yield susceptibility genes.
There are encouraging results from a variety of approaches.
One is to scan all the human chromosomes, the rodlike structures that hold genes, for locations that show evidence of harboring an autism gene. That involves analyzing inheritance patterns for particular bits of DNA along the chromosomes.
A half-dozen of these scans have been done for autism, and while results have not been uniform, researchers say at least two locations show promise. The big job now, of course, is to search those locations to identify any autism genes they hold. The hunt is already on.
Scientists also are pursuing clues from some accidents of nature. Researchers at UC Irvine, for example, recently reported finding that a girl with the condition had been born without a chunk of chromosome 15. So genes found in that chunk become candidates for study.
The proposed autism gene that grabbed headlines in November resulted from a different approach. A mutant mouse and a good memory put Patricia Rodier of the University of Rochester School of Medicine and Dentistry onto a gene called HOXA1.
In 1995, she and colleagues examined the brain stem of a woman with autism who had died in the 1970s. The brain stem had developed in a peculiar way, they found --as if a particular band of tissue had been removed and the adjacent areas had simply moved together.
Rodier realized she’d seen this pattern before, in a paper about mice with a disabled version of a gene that helps the brain stem develop.
The next step was to inspect the human version of that gene, called HOXA1, in people. Rodier and colleagues reported in November that a particular version of the gene showed up in autism patients more often than predicted by chance, suggesting it may promote the disease.
Experts call the finding intriguing. But they caution that, like all initial work, it has to be confirmed by further studies. Schellenberg and his collaborators have already begun that follow-up research.
“I wouldn’t be trying to replicate it if I didn’t think there was a pretty good chance it was true,” Schellenberg said.
So now, more than a half-century after American psychiatrist Leo Kanner gave autism its name, researchers may be closer to the genetic roots of the disorder. And a quest that looked so deceptively easy just a few years ago may finally pay off.
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Information on Autism:
https://www.ninds.nih.gov/health_and_medical/pubs/autism.htm
Autism Genetic Resource Exchange:
https://www.agre.org
National Alliance for Autism Research: https://www.naar.org
Autism Society of America:
https://www.autism-society.org
