Cause for Tourette syndrome suspected to be a single gene mutation
A new avenue for understanding Tourette syndrome, the complex disorder that causes muscle and vocal tics has been opened by researchers who have identified the first gene mutation associated with it.
Till date, causes of Tourette syndrome (TS), which afflicts as many as 1 in 100 people, have eluded researchers as the disease appeared to be caused by subtle mutations in many genes.
The findings were published in the October 14, 2005, issue of the journal Science with Matthew W. State of the Yale University School of Medicine as senior author of the paper. His research was supported by a Howard Hughes Medical Institute institutional award to Yale which had been used to support early research by promising scientists at Yale.
Other co-authors at Yale included HHMI investigator Richard P. Lifton, and neurobiologists Nenad Sestan and Angeliki Louvi from the Yale Child Study Center. The Yale scientists also collaborated with researchers from the University of California San Diego, Harvard Medical School, University of Missouri-Kansas City, University of Alabama at Birmingham, Johns Hopkins University School of Medicine and Cincinnati Children's Hospital Medical Center.
"There has been an evolving hypothesis about Tourette syndrome being a much more complex disorder," State said. "I think there is general consensus at this point that there are likely to be multiple genes, likely interacting, and probably different sets of genes in different people, that contribute to TS." The complex phenotype of the syndrome, which is often associated with obsessive-compulsive disorder, attention deficit hyperactivity disorder, or depression has lead to the notion of multiple gene mutation origin of the disease according State.
In order to search for a TS-related gene the same approach as used by Lifton to search for causative genes involved in cardiovascular, renal, and bone diseases was adopted. "We took a page from Rick's playbook in that we looked for unusual patients who have an identifiable genetic anomaly that we could trace to TS," said State.
A boy who was the only member of his family with TS and who had a gene inversion on chromosome 13 was then discovered by the researchers. This is usually the case
when a section of chromosome is broken off and reshuffles or reassembles before reinserting itself back into the chromosome.
State and his colleagues identified one gene, called SLITRK1 (for Slit and Trk-like family member 1), that is actively expressed in the brain and is associated with the growth and interconnection of neurons. The researchers screened 174 more people with TS, comparing their SLITRK1 gene to that of individuals without TS. They found one characteristic SLITRK1 mutation in affected members of one family that was absent in unaffected members. The mutation was however not found in another 3,600 chromosomes from people without TS that they analyzed.
In two people with TS, the researchers found
Another variant sequence within SLITRK1 was found in two people with TS, in a region of the gene that was not part of the direct blueprint for the SLITRK1 protein. "This was the strongest piece of genetic evidence in the research paper," said State. "We found two examples of exactly the same rare sequence change in a regulatory, non-coding region of the gene. And it was in two unrelated individuals with TS." Furthermore, the alteration which they called variant 321, was not found in 4,200 chromosomes from individuals without TS.
Variant 321 was found to be located in a region of the genome predicted to be involved in regulating SLITRK1 activity by interacting with molecules called microRNAs.
The researchers also found that a specific microRNA that regulates SLITRK1 binds to the genetic site of variant 321and both the SLITRK1 and the regulatory microRNA are expressed in regions of the brain believed to be involved in TS. Finally, when the researchers studied the function of SLITRK1 in cultures of neurons, they found that those with the normal gene showed longer connective branches, called dendrites, than did those with the mutation.
According to Lifton, "Matt's approach of looking for genetic outliers that contribute to the pathogenesis of Tourette's represents a new approach that has great potential to provide an avenue into the pathways that underlie this disease."
"The idea of looking for clues from chromosomal anomalies is a very powerful one that has paid off in this case," said Lifton. "The findings point for the first time to a pathway that appears to contribute to the pathogenesis of TS and enables further studies not only from a genetic perspective, but also from a pathophysiologic one."
State felt that even though the pathway that has been identified could prove important in understanding TS, "it still remains to be demonstrated by other labs whether aberrations in this pathway have pathological consequences in TS. Then we'll really pop the cork on the champagne, because this will give us an opportunity to begin to understand one pathway that -- while it may be responsible for only a small percentage of TS -- gives very concrete clues to disease mechanisms."