Inside this issueCover storiesMaking a major impact in ScienceNeuroscientists target disorders of the brain and spinal cordBanner year for Yale as six on faculty join Institute of MedicinePartnershipsNew collaboration with museum aims to improve science literacyYale, VA supporting troops on the home frontUnlikely allies, common goals in fight against obesityMedical school welcomes first Gilliam FellowsGrants & contractsPeopleLifelines: Edward Chu, moving cancer drugs into the clinicGraduate council bestows top honor on residency deanL. Veronica Lee champions prevention and women’s cardiovascular healthCell biologist Mellman elected to European academyAlumnus receives Yale Medal for his decades of serviceOut & aboutScienceAdvances: Restoring flexibility to heal broken brains | Mad cow’s small impact explained?HealthAdvances: Take sleep apnea seriously, says study | Cool therapy helps after troubled births 
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Making a major impact in ScienceTourette’s discovery hailed as breakthroughWhen 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.” Dyslexia gene also cited among journal’s top 10Long before a child enters school, brain cells are on the move, lining up into carefully wired circuits in preparation for the demanding task of learning to read. Mistakes in this circuit architecture are thought to underlie dyslexia, a reading disability that affects as many as 15 percent of children and runs strongly in families. In a finding that received worldwide recognition, Yale researchers have discovered a gene that may cause many cases of dyslexia by interfering with early brain development. The gene, DCDC2, is required for neurons to migrate normally and is disrupted in up to 20 percent of people with dyslexia. “Our results validate and confirm the fact that dyslexia is genetic,” says senior researcher Jeffrey R. Gruen, M.D., associate professor of pediatrics and an investigator at the Yale Child Health Research Center. “Based on brain imaging data, we know that dyslexics seem to have a disrupted brain reading circuit, and we think that variants of DCDC2 could be responsible for disrupting circuit formation during development.” Besides illuminating the cause of dyslexia, the identification of DCDC2 could lead to genetic tests to identify at-risk children early on, when educational interventions are most effective, Gruen says. The work, presented at the October meeting of the American Society for Human Genetics, was published in the November 22 issue of the Proceedings of the National Academy of Sciences. Dyslexia is defined as an impairment in reading ability in people with normal intelligence and adequate educational opportunities. For the last 15 years, researchers have been on the trail of a gene for dyslexia they had traced to human chromosome 6. In 2002, Gruen and colleagues narrowed the search to a stretch of 1.5 million DNA base pairs containing 19 candidate genes, all of which were known to be active in the brain.
(Left) Nerve cells have migrated in an orderly fashion toward the outermost layer of the cortex (top of photo) in the brain of a normal 14-day-old embryonic rat. But neurons in a littermate in which the DCDC2 gene has been suppressed (right) show abnormal migration. To get a closer look at those 19 genes in normal readers and dyslexics, Gruen and his team analyzed 536 parents and children from 153 families, correlating DNA sequences with the children’s scores on a battery of reading and comprehension tests. They quickly saw that in children with low reading scores, sequence variations clustered most often in the area of DCDC2. The researchers hit pay dirt when they noticed that in some dyslexic subjects, one copy of the DCDC2 gene was missing nearly 2,500 “letters” of DNA code. This deletion is uncommon in the general U.S. population, but it was seen in nearly 20 percent of the study participants with dyslexia. The DCDC2 deletion does not affect the structure or function of the gene’s protein product, but Gruen and his colleagues believe it reduces the overall amount of messenger RNA, and hence protein, in nerve cells. They then demonstrated that neurons did not migrate properly in the developing brains of fetal rats in which DCDC2 expression was experimentally suppressed. While the team hasn’t yet confirmed that DCDC2 protein levels are lower in dyslexic people, they did establish that in normal adult humans the gene is most active in brain regions that are involved in reading. The newly found gene has no relation to IQ, Gruen is quick to point out. And thanks to the flexibility of the brain’s circuitry early in life, he says that, with early intervention, dyslexic children may be able to compensate for their disability by training neural circuits other than those affected by the gene when they learn to read. “If children with dyslexia can get the right education program early
on, they will be successful,” Gruen says. “We’re hoping that someday we
can use genetic information to match kids to their ideal intervention as
early as possible.” 
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Medicine@Yale publication
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January/February 2006 Volume 2 Issue 1
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