When French neurologist Gilles de la Tourette first cataloged the persistent muscle tics and involuntary vocal outbursts characteristic of the syndrome that now bears his name, he recognized that the condition ran in families. Now, 120 years later, Yale researchers led by Matthew W. State, M.D., Ph.D., Harris Assistant Professor of Child Psychiatry, have identified the first genetic mutation associated with Tourette’s syndrome (TS).

Along with a Yale study of dyslexia (see “Dyslexia Gene Also Cited among Journal’s Top 10”), the work was cited in a list of the top 10 scientific breakthroughs of 2005 in the December 23 issue of the journal Science.

The gene, which contributes to neuronal development and communication between neurons, accounts for only a small percentage of cases of Tourette’s syndrome, but its discovery after years of searching offers the best chance yet to penetrate this socially debilitating condition.

Geneticists have been hunting unsuccessfully for genes involved in TS for decades. The disorder, which begins in adolescence, is relatively common, affecting as many as 1 per-cent of children. But symptoms of TS often overlap with other common diagnoses, including obsessive-compulsive disorder and attention-deficit hyperactivity disorder (ADHD), and there are almost certainly multiple genes that may all lead to increased risk for TS. Add to that the tendency of adults with TS to marry others with similar conditions, and the task of tracking suspect genes through extended families, a staple of genetic analysis, becomes extremely difficult.

To simplify the problem, State adopted a strategy pioneered by his Yale colleague, Chair and Sterling Professor of Genetics and Howard Hughes Medical Institute investigator Richard P. Lifton, M.D., Ph.D. “Rather than trying to group together families that may not have the same genetic contribution to TS,” State says, “we looked for that one unusual patient who would lead us to a gene.”

As reported in the October 14 issue of Science, the approach paid off when State’s group found a child with both TS and ADHD who had a telltale break on chromosome 13. Alerted by that defect, researchers suspected that there might be a problem with a nearby gene known as SLITRK1, because animal studies had already shown that SLITRK1 plays an important role in brain development. When the team analyzed 174 people with TS, they found three with mutations in SLITRK1. No mutations were found in several hundred unaffected people, providing strong evidence that SLITRK1 was contributing to the disease.

A close collaboration between State and Nenad Sestan, M.D., Ph.D., assistant professor of neurobiology, allowed the researchers to quickly determine the biological consequences of one of these mutations. Using sophisticated in utero gene delivery techniques, Sestan introduced either normal SLITRK1 or a gene with one of the mutations found in the subjects with TS into developing mouse neurons. The intact gene caused the neurons to branch out, a necessary step for the proper wiring of neural circuits early in life. But the mutated gene did not support normal branching.

The other mutation, found in two people with TS in the study, was nearly overlooked by the researchers because it occurred in a regulatory part of SLITRK1 that does not affect protein structure. But further investigation showed that this mutation was not present in several thousand unaffected individuals, and the team’s additional experiments suggest that the mutation may cause a lower level of the SLITRK1 protein to be present in some nerve cells in those with TS.

The newfound mutations are rare—only 2 percent of those with TS in the study had them—and how the mutations combine with genetic or environmental factors to increase risk for the disease is unknown. But SLITRK1 gives researchers a long-awaited starting point for further genetic investigations, says State, who likens the findings to a string that TS researchers can pull to begin unraveling the mysteries of the disorder.

“This is just the first piece of the puzzle,” State says. “We hope the clues this gene will give us will have widespread ramifications for understanding the basic biology of this disorder.”