Multiple rare mutations within a single gene may increase risk for autism, according to James Sutcliffe, PhD, and Randy Blakely, PhD, of the Vanderbilt Center for Molecular Neuroscience and the Vanderbilt Kennedy Center for Research on Human Development in Nashville. The findings also may point to new therapeutic options for autism, they suggested.

In a pair of studies, the investigators identified and characterized a number of mutations in the gene that regulates brain levels of serotonin. About 25% of people with autism have elevated levels of serotonin in their blood. Selective serotonin reuptake inhibitors (SSRIs) improve some of the symptoms of the disorder, leading investigators to propose that serotonin plays an important role in autism.

SERT-AIN RESULTS

In the August American Journal of Human Genetics, Dr. Sutcliffe and colleagues reported that several mutations within the serotonin transporter (SERT) gene, which regulates serotonin levels in the brain, may be risk factors for autism.

One variation in the SERT gene has been extensively studied and previously led to an inconclusive association with autism. No other variation stood out as a strong risk factor for the disorder. Dr. Sutcliffe’s work had detected a strong linkage between autism and the spot on chromosome 17 where the SERT gene resides. A few common variants or versions of this gene were known but did not seem to impart increased risk of autism.

“We failed to see evidence for a common version of the SERT gene that is the same in a majority of people,” said Dr. Sutcliffe, Associate Professor of Molecular Physiology and Biophysics and the lead investigator of the study. “So, either this was not the gene, or there had to be different genetic variants that were acting differently in different people.”

Prompted by this hypothesis, the investigators decided to dig deeper into the DNA sequence of the SERT gene to identify these rare mutations and to assess their role in autism risk. Using DNA samples from 120 families likely to possess a genetic risk factor on chromosome 17, the team found 19 different SERT mutations in families with multiple affected males, consistent with the well-known sex bias in autism incidence.

Four of these variants were in coding regions of the gene; the other 15 variants were in noncoding regions. “These coding mutations tracked with an increased severity of rigid-compulsive behaviors,” Dr. Sutcliffe explained. The findings underscore the relationship between autism and disorders like obsessive-compulsive disorder and may explain why SSRIs are effective in treating these conditions, he added.

A LACK OF COMMUNICATION

Strengthening the case for autism-linked SERT variants, in the August 9 Proceedings of the National Academy of Sciences, Dr. Blakely and colleagues described regulatory problems in SERT gene variants, suggesting a possible mechanism for how SERT mutations may disrupt serotonin signaling in autism. “We show that there are specific signaling pathways that cannot talk to SERTs with these mutations,” said Dr. Blakely, Allan D. Bass Professor of Pharmacology and senior author of the study.

Initially, Harish Prasad, PhD, a postdoctoral fellow in Dr. Blakely’s laboratory, examined 10 different SERT variants to determine how well they functioned. With the exception of one variant common to both studies, most of these variants had not been previously linked to any clinical conditions, Dr. Blakely noted.

While the variant SERTs could perform their basic function of clearing excess serotonin, the protein kinase G (PKG) and p38 mitogen-activated protein kinase (p38 MAPK) intracellular signaling pathways that normally fine-tune SERT activity were unable to control five of the 10 mutant SERT proteins examined, the investigators reported. “We were stunned because the cell just can’t ‘talk’ to these SERT proteins in a normal way,” Dr. Blakely said. “Although it’s impossible to extrapolate from a molecule to a person, it is striking that these mutations, which do not allow proper communication with SERT, show up in a disorder fraught with communication problems.”

THERAPEUTIC POTENTIAL

Drugs that target the p38 MAPK and PKG pathways have been investigated in a number of disorders unrelated to autism, such as inflammation and cancer. Targeting these pathways might offer a new alternative for treating autism with medications. “This is a potential therapeutic area that we had not envisioned before,” Dr. Blakely said.

Based on their findings, Drs. Blakely and Sutcliffe predict that there will one day be a way to test children with autism for the presence of these gene variants, similar to the testing done for cystic fibrosis, a disease linked to a single gene but triggered by many different mutations. “Autism has such a high genetic risk, but these new findings suggest that there may be many variants of individual genes at work,” Dr. Blakely said.

With such genetic testing, Dr. Sutcliffe added, “you might be able to predict which kids would respond positively to particular SSRI medications.”

“We now have concrete evidence in our families that the SERT gene is a risk factor in autism,” Dr. Blakely concluded. “Perhaps more importantly, we also have new pathways that could have some therapeutic end points, and that, to us, is really good news.”

Suggested Reading
Prasad HC, Zhu CB, McCauley JL, et al. Human serotonin transporter variants display altered sensitivity to protein kinase G and p38 mitogen-activated protein kinase. Proc Natl Acad Sci U S A. 2005;102:11545-11550.
Sutcliffe JS, Delahanty RJ, Prasad HC, et al. Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. Am J Hum Genet. 2005;77:265-279.

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