Tau is a candidate gene for chromosome 17 frontotemporal dementia

Abstract

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 ( Val 279 Met ) was found in one FTDP‐17 family but not in the second FTDP‐17 family. Three lines of evidence indicate that the Val 279 Met 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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Affiliated Institutions

• University of Washington Medical Center US
• Geriatric Research Education and Clinical Center US
• University of Washington US
• Binghamton University US
• Eunice Kennedy Shriver Center US
• VA Puget Sound Health Care System US
• University of Puget Sound US
• University of California, San Diego US

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