Gene Discovery in Tourette Syndrome through Homozygosity Mapping of Consanguineous Pedigrees

Grant Type
Grant Year
Institution Location
Institution Organization Name
Yale Child Study Center
Investigators Name
State, Matthew, MD, PhD

Two years ago, child psychiatrist, Dr.State won the TSA’s Young Investigator Award for his studies of rare genetic mutations in TS. In the October 14, 2005 issue of Science, Dr. State’s group reported findings suggesting that a gene on Chromosome 13 is associated with some forms of TS. This gene is expressed in several brain regions—including the cortex and basal ganglia. Both of these regions have already been implicated in causing TS symptoms. The evidence that this gene is associated with some forms of TS comes from several different findings. The study focused on a boy with TS who had an inversion of Chromosome 13—a “chunk” was flipped over. When this happened, included in the genes near the abnormal breakpoint of the chromosome was one (SLITRK1) that is expressed in the cortico-basal ganglia circuits implicated in TS. SLITRK1 makes a protein that normally spans cell membranes and has a characteristic region rich with the amino acid leucine (“leucine-rich repeat,” or “LRR”). Significantly,this region is quite similar in structure to a protein (SLIT1) that is known to promote the early development of neurons and guide their connections. State’s group then looked for abnormal SLITRK1 genes in 174 other affected TS cases.They found one patient who had a “frameshift mutation”—a misalignment of the DNA sequence—which leads to a loss of a significant portion of the protein product of the gene.This patient’s mother was diagnosed with an OCD-type disorder—trichotillomania—and she too carried this same “frameshift mutation.”Three other family members were unaffected with TS-like disorders, and importantly, they lacked this mutation. State’s group then screened many thousands of control chromosomes, and found no other examples of the frameshift. His group also checked to see whether they could find any potentially harmful sequence changes in this gene in an additional 253 unaffected individuals. None were found. Thus the evidence for supporting the association between having a “bad” copy of the gene and having TS was scientifically corroborated. Moreover, two other affected but unrelated individuals were found to have an identical change in the DNA sequence of SLITRK1 that would be predicted to result in deficient expression of the gene. State’s group tested this prediction in a cell culture and showed that this abnormal variant did indeed inhibit SLITRK1 expression because of an abnormal interaction with a second molecule called miR-189. They next reasoned that if what they had found was contributing to TS in these patients, there should be an overlap in the area where SLITRK1 and this second molecule (miR-189) would be found in the developing brain. They confirmed this overlap in both mouse and human fetal brain tissue located within the cortical projection neurons that form the cortico-basal ganglia connection. Next they again sought confirmation and found that the abnormality could not be found in more than 4000 chromosomes from normal individuals. Finally, as further corroboration, brain cells were grown in culture with the addition of either the full SLITRK1 protein or the shortened protein resulting from the frameshift mutation.They observed that the cells with normal SLITRK1 grew significantly longer dendrites (the brain cells’ “antennae”) when compared to cells with the abnormal “frameshift.” This systematic and comprehensive series of studies shows that, in at least some isolated cases,and even some families, TS is associated with a mutation that interrupts the normal function of the SLITRK1 gene. Furthermore, such an effect would alter cell development in a manner that would fit perfectly with what we know about the neurobiology of TS. While SLITRK1 is certainly not “the only” gene causing TS, these studies provide very strong evidence that this gene could contribute to some forms of TS. More importantly, it has the potential to teach us tremendous amounts about the biology of developmental insults that alter the brain in a manner that ultimately leads to causing TS. With this funding from the TSA, Dr. State will now develop and investigate a mutant mouse in which the SLITRK1 gene is inactivated. In this work, he will collaborate with Dr. Nenad Sestan, a previously TSA-funded scientist at Yale. This mutant mouse will be the first known to carry a gene that has been identified to be abnormal in some individuals with TS. TSA’s support will allow Dr. State and his team to examine the impact of this genetic mutation on normal brain development. Although this project is a logical “next small, but critical step,” it is also potentially a “giant leap” for the broader field of TS science. It is an exciting development and will undoubtedly bring about much progress in our efforts to identify the causes of, and improved treatments for this disorder. — Neal R. Swerdlow, Chair, TSA Scientific Advisory Board Matthew State, M.D., Ph.D. Yale University Child Study Center, New Haven, Connecticut Award: $75,000 Tourette Association of America Inc. – Research Grant Award 2005-2006