In the April 2007 issue of the Journal of Clinical Investigation, researchers implicated a specific protein to autism, while work published in the March 15 online edition of Science showed that copy number variations in several genes also are tied to autism.
The JCI paper showed that in mice, mutations in a protein known as CADPS2, specifically its interactions with another protein known as dynactin 1, led to anatomical abnormalities in the cerebellum and behavioral changes that model those seen in autistics. When they screened autistic patients, they found that roughly a quarter of autistic patients they tested had mutations that took one exon out of the CADPS2 protein.
CADPS2 plays a role in secreting brain-derived neurotrophic factor or BDNF. The group's work suggests that when CADPS2 is missing its third exon, it does not accumulate in axons as usual.
"We hypothesize that a disturbance of CADPS2-mediated local BDNF release causes the abnormality in the neural network formation and function, which may contribute to autism susceptibility," senior author Teiichi Furuichi, head of the laboratory for molecular neurogenesis at the RIKEN Brain Sciences Institute in Saitama, Japan, told BioWorld Today. However, he cautioned that "at present . . . we have no direct evidence on the aberrant distribution of CADPS2 in neurons of autistic patients."
The behavioral changes were fairly subtle. Mice did not show decreased exploration of an open platform, one of the most common ways of assessing anxiety, though they did show decreased social interaction and increased anxiety when measured by other experimental methods.
Furuichi said that his team was "not surprised" at the subtlety of the behavioral effects. "We did not expect too robust or severe changes in [knockout] mouse behaviors under ordinary conditions. Individuals with autism sometimes look just like anyone in the population."
While Furuichi's team focused on one specific protein, the work published in Science - co-led by Jonathan Sebat, Lakshmi Muthuswamy (who publishes as B. Lakshmi,) and Michael Wigler at the Cold Spring Harbor Laboratory in New York - looked at copy number variations across a larger region of the genome. The authors found that 10 percent of autism patients had such copy number variations, as opposed to 2 percent and 1 percent of the members of two control groups, respectively.
The Science paper comes about a month after a Nature paper that also implicated copy number variations in autism. (See BioWorld Today, Feb. 21, 2007.)
The fact that copy number variations in a variety of genes may converge on the behaviors that characterize autism spectrum disorders also could explain another of autism's puzzles: why there are "no great cellular and anatomical abnormalities in autistic patients' brains," as Furuichi phrased it.
When asked about clinical implications of the work, Furuichi mentioned diagnosis before drug discovery; earlier diagnosis is certainly helpful for treating autistics. However, he also believes findings could suggest a target for an autism drug. Furuichi said he expects the findings "to open a new window toward the development of a clinical treatment for autism, e.g., drugs that act [on] the CADPS2-mediated local release of BDNF."
Michael Wigler, senior author of the Science paper, thought his and his colleagues' work was more relevant to the diagnostics side. "There is an outside chance that we will hit a jackpot in terms of an obvious drug target," he told BioWorld Today. But "the main practical consequences of this in the near future" probably lie in the area of genetic counseling and diagnosis.