Identification and Characterization of Asymmetrically Expressed Genes in the Human Cortex

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 have symptoms. Although none of these mutations accounts for a large proportion of TS cases, the study of each rare determinant may provide important clues as to why TS occurs. In one such report, a mutation in a gene called CASPR2 was seen in children with TS. We became interested in CASPR2 after performing a large gene expression study in the developing human brain. In this work, we looked at a number of genes and asked where in the brain each was normally present. We determined that the distribution (or expression pattern) of CASPR2 recapitulated a well-characterized anatomical pathway involved in both TS pathogenesis and the control of voluntary behavior. This finding is exciting because it suggests that expression of CASPR2 may be necessary for normal regulation of higher order decision-making. Taken together with the above mentioned report, these results suggest that CASPR2 could be implicated in TS. To test directly whether mutations in CASPR2 can result in TS-like features, we are evaluating whether mice with a mutation in this gene show symptoms of disease. Although mice and humans differ in many ways, mutations known to affect brain development and behavior in one species often have a similar effect in the other. Moreover, a large body of work suggests that the circuitry implicated in TS is well conserved between the two species. Specifically, we are looking for a variety of TS-like abnormalities, including vocal and motor tics, in CASPR2 mutant mice. We are also characterizing the expression patterns of a number of TS candidate genes to determine whether any of these molecules show altered distribution in the presence of a CASPR2 mutation. Because animal models for the disorder are lacking, the identification of abnormalities in these mutant mice would greatly facilitate research aimed at understanding the mechanisms underlying TS. Brett S. Abrahams, Ph.D. University of California at Los Angeles, Los Angeles, California Award: $40,000 Tourette Association of America Inc. – Research Grant Award 2006-2007