Tourette syndrome is a complex neurological disorder for which segregation analyses consistently support an autosomal dominant mode of transmission. The gene for this disease is unknown, and has not been linked to a specific chromosomal location. The limited neuropathology of Tourette syndrome (TS) includes decreased levels of a dopaminergic metabolite in the cerebrospinal fluid and an increase in dopamine uptake sites in the striatum. These findings, and others, suggest changes in dopaminergic innervation of the striatum in TS patients, which may be due to abnormalities in neurotrophic factors for dopaminergic neurons. The objectives of this research are to determine if neurotrophic factors play a role in the etiology of TS and to identify the gene for TS. It is important to understand the etiology of TS and to identify the TS gene to enable the development of: 1) diagnostic screening assays, 2) more tightly directed therapies with fewer side effects than current therapies, and 3) treatments that could cure, or ameliorate the progress of, the disease.
The specific aims are; 1. Purify the protein for the dopaminergic neurotrophic factor, amnion- derived neurite-promoting factor (ANPF), and clone, sequence, and map the gene for ANPF. 2. Find segregating variants in the regions of candidate dopaminergic neurotrophic factor genes in DNA from TS families. The candidate genes include the genes for ANPF and glial cell line-derived neurotrophic factor, whose mapping is proposed in this study, as well as the already mapped genes for brain-derived neurotrophic factor, basic fibroblast growth factor, and interleukin-1. 3. Further define the dopaminergic neurotrophic effects of ANPF on central nervous system ventral mesencephalon dopaminergic neurons. 4. If linkage is shown, pursue appropriate studies to clone and identify the gene for TS. The resources, training and environment available to ensure successful completion of this research includes: DNA from individuals in two large TS kindreds; significant genetic mapping and typing of these families; the scientific expertise and state-of-the-art equipment present in a leading laboratory in the field of molecular biology and the genomic analysis of neurogenetic disorders; graduate level courses in molecular and genetic analyses; collaborative opportunities with other laboratories in molecular neurobiology; and many core facilities. The successful completion of this research will lead to a clearer understanding of the role of neurotrophic factors in one specific neurological disease, and provide the molecular biological training needed by the principal investigator to pursue her goal of better understanding the molecular and genetic regulation of neurite-outgrowth during development, in disease, and after injury.
| Palmatier, M A; Kang, A M; Kidd, K K (1999) Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles. Biol Psychiatry 46:557-67 |
