Tourette Disorder (TD) is a developmental neuropsychiatric syndrome defined by the presence of chronic vocal and motor tics that affects as many as 1 in 100 school aged children. Despite considerable evidence for a genetic contribution, no disease-related genes have been identified. SLIT and Trk-like family 1 (SLITRK1) has recently been found to be a strong candidate for involvement in TD, initially through the mapping of a de novo chromosomal abnormality in the only affected member of a three-generation pedigree. Mutation screening of 204 probands subsequently identified: 1) a truncating frameshift mutation that was present in two affected, and absent in three unaffected family members, and could not be found in 3600 control chromosomes;2) A non-synonymous substitution at a highly conserved amino acid in the transmembrane domain in 2 affected siblings, not present in 4000 control chromosomes;and 3) in two unrelated individuals, the identical single base substitution at a highly conserved nucleotide in the binding domain for the brain expressed microRNA-189 (miR-189), not present in 4296 control chromosomes. Expression analysis demonstrates that SLITRK1 mRNA and miR-189 overlap in brain regions thought relevant to the pathogenesis of TD. Overexpression of wild-type Slitrkl, but not the frameshift mutant, in developing cortical neurons promotes dendritic elongation. We now propose to investigate further the role of SLITRK1 in TD through a continued cross-disciplinary collaboration involving pediatric psychiatry, genetics and neurobiology. Specifically we aim to: 1) search for additional mutations in SLITRK1 in an expanded group of patients with TD and related disorders;2) further characterize the expression of SLITRK1 RNA and protein in developing mouse and human brain;3) elaborate the function of wildtype and mutant SLITRK1 in developing cortical neurons;and 4) identify proteins that interact with SLITRK1 as a prelude to mutation screening of these genes. SLITRK1 is a gene implicated in some cases of Tourette Disorder (TD) by the finding of rare DNA sequence changes in a small number of patients that have not been found in unaffected persons. The purpose of this study is to better understand .what causes TD by identifying additional abnormalities in the SLITRK1 gene and by investigating the impact of these unusual genetic changes on the developing brain.
| Baldan, Lissandra Castellan; Williams, Kyle A; Gallezot, Jean-Dominique et al. (2014) Histidine decarboxylase deficiency causes tourette syndrome: parallel findings in humans and mice. Neuron 81:77-90 |
| Wu, Steve W; Gilbert, Donald L (2012) Altered neurophysiologic response to intermittent theta burst stimulation in Tourette syndrome. Brain Stimul 5:315-319 |
| Klotz, Jenna M; Johnson, Matthew D; Wu, Steve W et al. (2012) Relationship between reaction time variability and motor skill development in ADHD. Child Neuropsychol 18:576-85 |
| Fernandez, Thomas V; Sanders, Stephan J; Yurkiewicz, Ilana R et al. (2012) Rare copy number variants in tourette syndrome disrupt genes in histaminergic pathways and overlap with autism. Biol Psychiatry 71:392-402 |
| Wu, Steve W; Shahana, Nasrin; Huddleston, David A et al. (2012) Effects of 30Hz ? burst transcranial magnetic stimulation on the primary motor cortex. J Neurosci Methods 208:161-4 |
| State, Matthew W (2011) The genetics of Tourette disorder. Curr Opin Genet Dev 21:302-9 |
| Bloch, Michael; State, Matthew; Pittenger, Christopher (2011) Recent advances in Tourette syndrome. Curr Opin Neurol 24:119-25 |
| Krusong, Kuakarun; Ercan-Sencicek, A Gulhan; Xu, Meiyu et al. (2011) High levels of histidine decarboxylase in the striatum of mice and rats. Neurosci Lett 495:110-4 |
| O'Roak, B J; Morgan, T M; Fishman, D O et al. (2010) Additional support for the association of SLITRK1 var321 and Tourette syndrome. Mol Psychiatry 15:447-50 |
| Klotz, Jenna M; Carvalho, Natalia R; Gilbert, Donald L et al. (2010) Electroencephalographic monitoring during hypothermia after pediatric cardiac arrest. Neurology 74:438; author reply 438-9 |
Showing the most recent 10 out of 15 publications
