sábado, 17 de abril de 2010

DOTmed.com - In Autism, Evidence for Gene Expression Gone Awry



In Autism, Evidence for Gene Expression Gone Awry
April 14, 2010
by Brendon Nafziger, Writer
Chemical changes to genes governing brain cell death, the body's daily rhythms, and muscle tone are linked to autism, according to a brace of new studies, offering promising new biomarkers and a target of treatment for the disorders.


A study appearing online in the FASEB Journal found that two genes were chemically "tagged" in a way that turned them off in autistic subjects, but not in their non-autistic identical twins and siblings. Differences in protein products of the genes were also found in parts of the brains of autistic subjects removed during autopsies, when compared with the brains of those without the disorder.

The genes, dubbed BCL-2 and RORA, showed evidence of epigenetic changes. Epigenetics is the study of hereditary changes in gene expression that don't involve alterations to the DNA sequence. In the study, the two genes in autistic subjects underwent a fairly well understood epigenetic process called methylation: that is, they had picked up extra methyl groups, causing the genes to be under-expressed.

TWIN MYSTERY

Epigenetics became an interesting target for the researchers because in many cases of identical twins only one is autistic. As identical twins have the same genes, this suggests that autism could not be fully genetic.

Plus, the sheer number of genes differently expressed between autistic and non-autistic controls in previous studies rules out a pure genetic explanation, according to Valerie Hu, Ph.D., senior author of the paper and a professor of biochemistry and molecular biology at George Washington University Medical Center in Washington, D.C. In one severe type of autism, involving language impairment, thousands of genes are differently expressed when compared with non-autistic controls, she says.

"You can't possibly have hundreds or thousands of mutations," Hu tells DOTmed News. "The most likely explanation is you're having disruption of epigenetic mechanisms that control batteries of genes."

TWO GENE CANDIDATES

For the study, the researchers looked at cell lines taken from three pairs of identical male twins where one twin was diagnosed with an autism spectrum disorder (ASD), but the other wasn't (though, typically, the other twin showed mild symptoms too subtle to merit a clinical ASD diagnosis). They then looked at cells from non-autistic volunteers, as well as, for two of the pairs, cells from non-autistic siblings.

For more precise measurements of protein expression in the brain, they also examined slices taken from the brains of cadavers -- autistic and non-autistic -- carefully matched for age and sex.

For both the living and the dead, BCL-2 and RORA were decreased in samples from autistic persons.

Tellingly, these genes are associated with processes that appear to play a role in autism. BCL-2 is a gene believed to stop cell death in the brain. Earlier studies have shown it is 34 to 51 percent less expressed in autistic male brains than in control subjects. RORA regulates the body's circadian rhythms; it also controls muscle tone and shields brain cells from the harmful effects of inflammation and oxidative stress. Importantly, it's also involved in the development of the cerebellum, a part of the brain known to be affected in autism.

Although RORA has never before been implicated in ASD, Hu says a naturally mutated mouse studied for its lack of coordination of muscle movement, which suffers from RORA deficiencies, shows autistic-like behaviors, such as reduced maze exploration and repetitive movements.

But these two genes might just be the tip of the iceberg. In another study also published by Hu and her team last week, in Genome Medicine, they found widespread differences in microRNA in ASD subjects when compared with controls. MicroRNA are snippets of RNA that turn off RNA molecules, limiting their expression. Of the 43 microRNA changes found in ASD subjects, 16 were brain-related. Others were linked with muscle disorders and gastrointestinal disturbances, a controversial and not universally accepted symptom of autism.

CAUSE UNKNOWN

Hu, whose 22-year-old son was diagnosed with an ASD, admits they're not sure what makes the gene expression go awry.

"No one really understands, or knows, what the environmental factors are that might predispose to autism; that's the bottom-line, that we don't know enough," says Hu. "There's no substitute for knowledge in terms of saying one thing or another. The fact is, we just don't know enough about genes, we don't know enough about epigenetic mechanisms."

Her team is now planning future studies to see what environmental or biological risks might predispose vulnerability to the disorder.

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DOTmed.com - In Autism, Evidence for Gene Expression Gone Awry

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