Tau is a candidate gene for chromosome 17 frontotemporal dementia

Authors

  • Parvoneh Poorkaj PhD,

    1. Geriatric Research Education Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, University of Washington, Seattle, WA
    2. Divisions of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA
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  • Thomas D. Bird MD,

    1. Geriatric Research Education Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, University of Washington, Seattle, WA
    2. Department of Neurology, University of Washington, Seattle, WA
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  • Ellen Wijsman PhD,

    1. Divisions of Medical Genetics, University of Washington, Seattle, WA
    2. Department of Medicine, University of Washington, Seattle, WA
    3. Department of Biostaistics, University of Washington, Seattle, WA
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  • Ellen Nemens MS,

    1. Geriatric Research Education Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, University of Washington, Seattle, WA
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  • Ralph M. Garruto PhD,

    1. Department of Anthropology, Binghamton University, SUNY, Binghamaton, NY
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  • Leojean Anderson BS,

    1. Geriatric Research Education Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, University of Washington, Seattle, WA
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  • Athena Andreadis PhD,

    1. E. K. Shriver Center for Mental Retardation, Walthem, MA
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  • Wigbert C. Wiederholt MD,

    1. Department of Neurosciences, University of California at San Diego, CA
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  • Murray Raskind MD,

    1. Department of Psychiatry, Veterans Affairs Puget Sound Health Care System, Seattle Division, University of Washington, Seattle, WA
    2. Department of Psychiatry, University of Washington, Seattle, WA
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  • Gerard D. Schellenberg PhD

    Corresponding author
    1. Geriatric Research Education Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, University of Washington, Seattle, WA
    2. Divisions of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA
    3. Department of Neurology, University of Washington, Seattle, WA
    4. Department of Pharmacology, University of Washington, Seattle, WA
    • GRECC 182-B, Veterans Affairs Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA 98108
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Abstract

Frontotemporal dementia with parkinsonism, chromosome 17 type (FTDP-17), a recently defined disease entity, is clinically characterized by personality changes sometimes associated with psychosis, hyperorality, and diminished speech output, disturbed executive function and nonfluent aphasia, and rigidity. Neuropathological changes include frontotemporal atrophy often associated with atrophy of the basal ganglia, substantia nigra, and amygdala. Neurofibrillary tangles (NFTs) are seen in some but not all families. Inheritance is autosomal dominant and the gene has been regionally localized to 17q21-22 in a 2- to 4-centimorgan (cM) region flanked by markers D17S800 and D17S791. The gene for tau, the primary component of NFTs, is located in the same region of chromosome 17. Tau was evaluated as a candidate gene. Physical mapping studies place tau within 2 megabases or less of D17S791, but it is probably outside the D17S800-D17S791 FTDP-17 interval. DNA sequence analysis of tau coding regions in affected subjects from two FTDP-17 families revealed nine DNA sequence variants, eight of which were also identified controls and are thus polymorphisms. A ninth variant (Val279Met) was found in one FTDP-17 family but not in the second FTDP-17 family. Three lines of evidence indicate that the Val279Met change is an FTDP-17 causative mutation. First, the mutation site is highly conserved, and normal valine is found at this position in all three tau interrepeat sequences and in other microtubule associated protein tau homologues. Second, the mutation co-segregates with the disease in family A. Third, the mutation is not found in normal controls.

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