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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS056276-04
Application #
7675963
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Mamounas, Laura
Project Start
2006-09-01
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
4
Fiscal Year
2009
Total Cost
$416,044
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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
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
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
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
State, Matthew W (2010) The genetics of child psychiatric disorders: focus on autism and Tourette syndrome. Neuron 68:254-69
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

Showing the most recent 10 out of 15 publications