The genetics of chromosome 17q21-linked tau-negative FTD

  • Petrucelli, Leonard (PI)
  • Hutton, Michael L. (PI)
  • Hutton, Michael L. (PI)
  • Kinney, Lea (PI)
  • Kinney, Lea (PI)
  • Kinney, Lea (PI)

Project: Research project

Project Details

Description

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DESCRIPTION (provided by applicant): Frontotemporal dementia (FTD) is a heterogeneous condition characterized by early behavioral change, cognitive decline and atrophy of the frontal and temporal lobes. The microscopic pathology varies markedly in different forms of the disease with some cases having tau-positive neuronal inclusions. However, the majority of FTD cases (approximately 60%) lack tau-positive lesions displaying mainly a microvacuolization of the superficial neuropil in the cortex. A proportion of these cases (10-15%) however do have ubiquitin-positive inclusions in motor neurons and show evidence of motor neuron degeneration (MND) leading to their designation as FTD-MND cases. Genetic linkage studies in FTD families have revealed three loci on chromosomes 17, 3 and 9. Over 30 mutations in the tau gene account for the majority of autosomal-dominant chromosome 17-linked cases (FTDP-17). FTDP-17 patients with identified tau mutations develop tau neurofibrillary pathology and many families also develop tau inclusions in glial cells. It is becoming increasingly clear that a proportion of chromosome 17q21-linked families lack any apparent mutations in the tau gene and, moreover, do possess the neurofibrillary pathology seen in families with defined tau mutations. Importantly, these chromosome 17q21-linked families exhibit ubiquitin positive neuronal inclusions, and a intranuclear ubiquitin positive inclusions are also seen in certain pedigrees. It is possible that the genetic cause of these families results from an unidentified mutation in the tau gene e.g. deep within an intron or from gross alterations of the tau locus, such as duplication. Alternatively, this disease could be caused by an alternative gene in this region. The overall aim of this proposal is to identify gene mutations associated with tau-negative FTD with neuronal and intranuclear ubiqutin positive inclusion linked to chr17q21 and to study the genotype/phenotype relationship and pathogenic mechanism of mutations in this gene. The identification of this gene will be a crucial step towards understanding the etiology of FTD as well as determining how this disease relates to MND. [unreadable]
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StatusFinished
Effective start/end date9/1/063/31/15

Funding

  • National Institute on Aging: $284,898.00
  • National Institute on Aging: $301,480.00
  • National Institute on Aging: $301,480.00
  • National Institute on Aging: $382,500.00
  • National Institute on Aging: $313,650.00
  • National Institute on Aging: $301,480.00
  • National Institute on Aging: $188,181.00

ASJC

  • Medicine(all)

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