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Pick's disease associated with the novel Tau gene mutation K369I
Author(s) -
Neumann Manuela,
SchulzSchaeffer Walter,
Crowther R. Anthony,
Smith Michael J.,
Spillantini Maria Grazia,
Goedert Michel,
Kretzschmar Hans A.
Publication year - 2001
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.1223
Subject(s) - missense mutation , tau protein , exon , pick's disease , proband , mutation , frontotemporal dementia , neuropathology , biology , alzheimer's disease , pathology , dementia , genetics , medicine , disease , gene
Exonic and intronic mutations in Tau cause neurodegenerative syndromes characterized by frontotemporal dementia and filamentous tau protein deposits. We describe a K369I missense mutation in exon 12 of Tau in a patient with a pathology typical of sporadic Pick's disease. The proband presented with severe personality changes, followed by loss of cognitive function. Detailed postmortem examination of the brain showed atrophy, which was most pronounced in the temporal lobes; and numerous tau‐immunoreactive Pick bodies and Pick cells in the neocortex and the hippocampal formation, as well as in subcortical brain regions. Their appearance and staining characteristics were indistinguishable from those of sporadic Pick's disease. However, immunoblot analysis of sarkosyl‐insoluble tau showed three major bands of 60, 64, and 68 kDa, consistent with the presence of 3‐ and 4‐repeat tau isoforms, as in Alzheimer's disease. Isolated tau filaments were irregularly twisted ribbons, with a small number of Alzheimer‐type paired helical filaments. In the presence of heparin, tau proteins with the K369I mutation formed short, slender filaments. Biochemically, recombinant tau proteins with the K369I mutation showed reduced ability to promote microtubule assembly, suggesting that this may be the primary effect of the mutation by providing a pool of aberrant tau for filament assembly. Taken together, the present findings indicate that the K369I mutation in Tau can cause a dementing disease with a neuropathology like that of Pick's disease.