title: A new family with frontotemporal dementia with intronic 10+3 splice site mutation in the tau gene: neuropathology and molecular effects.
abstract: Mutations in the tau gene cause familial frontotemporal dementia with parkinsonism linked to chromosome 17 characterized by filamentous tau protein deposits. Here we describe the clinical and neuropathological features of a case from a newly identified family with an intron 10+3-splice site mutation in the tau gene. The proband presented with severe personality changes and stereotyped speech followed by parkinsonian symptoms. He died at age 56 after a disease duration of approximately 6 years. At autopsy, there was marked frontotemporal degeneration with abundant tau-immunoreactive neuronal and glial inclusions widespread in the cortex and brainstem. RT-PCR analysis revealed a 3.7-fold increase of tau transcripts with exon 10, resulting in an 1.7-fold higher expression level of 4-repeat tau isoforms in soluble tau fractions when compared to control brains and exclusively 4-repeat tau isoforms in the sarcosyl-insoluble tau fractions. In accordance with the hypothesis that the overexpression leads to saturation of microtubule binding sites and an increase of unbound 4-repeat tau isoforms which assemble into filaments, the neuronal and glial inclusions in this case were exclusively composed of 4-repeat tau isoforms. The clinical and neuropathological data of this family are compared with results from the two other published families with the intron 10 + 3 mutation, the MSTD and the SOT 254 family.
authors: Center for Neuropathology and Prion Research, Ludwig-Maximilians University, München, Germany.
authors: M
authors: M
authors: Neumann
authors: M
authors: M
authors: Mittelbronn
authors: P
authors: P
authors: Simon
authors: B
authors: B
authors: Vanmassenhove
authors: R
authors: R
authors: de Silva
authors: A
authors: A
authors: Lees
authors: J
authors: J
authors: Klapp
authors: R
authors: R
authors: Meyermann
authors: H A
authors: HA
authors: Kretzschmar
mesh_terms: D001483:Base Sequence; D001921:Brain / Q000473:pathology*; D004252:DNA Mutational Analysis; D003704:Dementia / Q000235:genetics* / Q000473:pathology*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D020033:Protein Isoforms / Q000235:genetics; D022821:RNA Splice Sites; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016875:tau Proteins / Q000235:genetics*
chemical_list: D020033:Protein Isoforms; D022821:RNA Splice Sites; D016875:tau Proteins