Abstract

A number of families (13) with fronto-temporal dementia and parkinsonism (FTDP) have been linked to the same (approx. 2 cM) region of chromosome 17q21. The clinical features of this disease include early behavioral change and motor manifestations leading to progressive memory loss and dementia. At autopsy, the patients with FTDP-17 all show fronto-temporal atrophy with neuronal cell loss, neruopil vacuolation and gliosis in both white and gray matter. Argyrophilic and/or tau positive neuronal inclusion are observed in some families. Ballooned neurons are found in all cases that have been examined to date. The overall of this study is to identify the gene for and the pathogenic mutations which cause FTDP-17. In order to perform this task the candidate region for FTDP-17 will be minimized using data from a series of FTDP-17 kindreds and the candidate region will be physically mapped in YACs and PACs. Known genes and ESTs will be mapped into the FTDP-17 region and then prioritized for study as candidates for FTDP-17. Sequence analysis of candidate genes (novel and previously identified, ie GFAP and tau) will be performed to identify mutations. Once the FTDP-17 gene has been identified the prevalence of the disease will be studied in both a prospective community-based dementia cohort in Rochester, Minnesota and in two autopsy cohorts.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037143-02
Application #
2839434
Study Section
Special Emphasis Panel (ZRG1-NLS-3 (01))
Program Officer
Oliver, Eugene J
Project Start
1997-12-01
Project End
2000-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Mayo Clinic, Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224

  Publications

DeTure, M; Ko, L W; Yen, S et al. (2000) Missense tau mutations identified in FTDP-17 have a small effect on tau-microtubule interactions. Brain Res 853:14-May
Duff, K; Knight, H; Refolo, L M et al. (2000) Characterization of pathology in transgenic mice over-expressing human genomic and cDNA tau transgenes. Neurobiol Dis 7:87-98
Baker, M; Litvan, I; Houlden, H et al. (1999) Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 8:711-5
Yen, S H; Hutton, M; DeTure, M et al. (1999) Fibrillogenesis of tau: insights from tau missense mutations in FTDP-17. Brain Pathol 9:695-705
Grover, A; Houlden, H; Baker, M et al. (1999) 5' splice site mutations in tau associated with the inherited dementia FTDP-17 affect a stem-loop structure that regulates alternative splicing of exon 10. J Biol Chem 274:15134-43
Yen, S; Easson, C; Nacharaju, P et al. (1999) FTDP-17 tau mutations decrease the susceptibility of tau to calpain I digestion. FEBS Lett 461:91-5
Morris, H R; Perez-Tur, J; Janssen, J C et al. (1999) Mutation in the tau exon 10 splice site region in familial frontotemporal dementia. Ann Neurol 45:270-1
Nacharaju, P; Lewis, J; Easson, C et al. (1999) Accelerated filament formation from tau protein with specific FTDP-17 missense mutations. FEBS Lett 447:195-9
Isaacs, A; Baker, M; Wavrant-De Vrieze, F et al. (1998) Determination of the gene structure of human GFAP and absence of coding region mutations associated with frontotemporal dementia with parkinsonism linked to chromosome 17. Genomics 51:152-4