Continued Evaluation of CNTNAP2/CASPR2 as a Tourette Syndrome Candidate Gene (2nd Year)

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of California
Investigators Name
Abrahams, Brett, PhD

Although the causes of Gilles de la Tourette syndrome (TS) are complex and largely unknown, strong evidence supports an important role for genetics in the modulation of disease risk. In support of this idea, rare families have been described in which a single genetic change (or mutation) appears to determine whether or not a person will show symptoms. Although none of these mutations account for a large proportion of TS cases, the study of each rare determinant may provide important clues as to why TS occurs. After performing a large gene expression study in the developing human brain, we became interested in one called CNTNAP2. In this work, we looked at a number of genes and asked where in the brain each was normally expressed. We determined that the distribution of CNTNAP2 recapitulated a well-characterized anatomical pathway involved in both TS pathogenesis and the control of voluntary behavior. This finding was exciting because it suggested that expression of CNTNAP2 may be necessary for normal regulation of higher order decisionmaking. Taken together with a report in which a mutation in CNTNAP2 was seen in children with TS, these results suggest that mutations in this gene may cause disease. Towards the development of an animal model of TS, we tested (with funding from the TSA) the extent to which distribution of CNTNAP2 was similar in mice and humans. Much to our surprise, very different results were observed between the two species—a finding of central importance toward our understanding of the disorder. To further explore the consequences of CNTNAP2 mutations on a genome-wide scale, we will determine whether disease-linked mutations alter transcript levels in mouse tissues and human cell lines. We are confident that these experiments will help flush out diseaserelated pathways amenable to therapeutic intervention Brett S. Abrahams, Ph.D. University of California at Los Angeles Los Angeles, CA Award: $40,000 (2nd Year) Tourette Association of America Inc. – Research Grant Award 2007-2008