The proposed project will map and clone the gene for frontotemporal dementia (FTD), a clinically and pathologically heterogeneous disorder that has been localized to chromosome 17q21-22. The PI and colleagues have identified a series of FTD families with significant linkage to this region, and they have narrowed the locus to 2-3 cM. They now propose to gather and analyze additional families through research centers in the US and Sweden. The additional families will be used to further delineate the disease locus by segregation analysis (identification of recombinants) and allelic association. The obligate genetic region will be physically mapped and cloned. Candidate genes will be identified from amongst transcripts already known to exist in the region and newly identified clones. The candidates will be prioritized by expression pattern, presence of CAG repeats, and sequence homology. The candidate genes will then be sequenced in FTD patient samples to identify mutations specific to the disease. After the gene is identified, further plans include genotype-phenotype correlation study, sequence analysis, and analysis of the effects of the mutations in vitro and in vivo.
| Webb, Amy; Miller, Bruce; Bonasera, Stephen et al. (2008) Role of the tau gene region chromosome inversion in progressive supranuclear palsy, corticobasal degeneration, and related disorders. Arch Neurol 65:1473-8 |
| Wilhelmsen, Kirk C; Forman, Mark S; Rosen, Howard J et al. (2004) 17q-linked frontotemporal dementia-amyotrophic lateral sclerosis without tau mutations with tau and alpha-synuclein inclusions. Arch Neurol 61:398-406 |
| Nasreddine, Z S; Loginov, M; Clark, L N et al. (1999) From genotype to phenotype: a clinical pathological, and biochemical investigation of frontotemporal dementia and parkinsonism (FTDP-17) caused by the P301L tau mutation. Ann Neurol 45:704-15 |
