title: A novel tau mutation in exon 9 (1260V) causes a four-repeat tauopathy.
abstract: A novel mutation in exon 9 of tau, I260V, is associated with a clinical syndrome consistent with frontotemporal dementia with extensive tau pathology; however, neurofibrillary tangles and Pick bodies are absent. Significantly, Sarkosyl-insoluble tau extracted from affected brain tissue consisted almost exclusively of four-repeat isoforms. Consistent with these findings, in vitro biochemical assays demonstrated that the I260V mutation causes a selective increase in tau aggregation and a decrease in tau-induced microtubule assembly with four-repeat isoforms only. The contrasting pathology and biochemical effects of this mutation suggest a different disease mechanism from the other exon 9 mutations and demonstrates the critical role for the first microtubule-binding domain in tau-promoted microtubule assembly and the pathogenic aggregation of tau.
authors.affiliation: Laboratory of Neurogenetics, Neuroscience Department, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Grover
authors.forename: Elisabet
authors.initials: E
authors.lastname: England
authors.forename: Mathew
authors.initials: M
authors.lastname: Baker
authors.forename: Naruhiko
authors.initials: N
authors.lastname: Sahara
authors.forename: Jennifer
authors.initials: J
authors.lastname: Adamson
authors.forename: Brian
authors.initials: B
authors.lastname: Granger
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.forename: Ulla
authors.initials: U
authors.lastname: Passant
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Yen
authors.forename: Michael
authors.initials: M
authors.lastname: DeTure
authors.forename: Michael
authors.initials: M
authors.lastname: Hutton
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D004247:DNA / Q000235:genetics; D003704:Dementia / Q000235:genetics* / Q000473:pathology*; D005091:Exons / Q000235:genetics; D005625:Frontal Lobe / Q000473:pathology*; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008870:Microtubules / Q000648:ultrastructure; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013702:Temporal Lobe / Q000473:pathology*; D016875:tau Proteins / Q000235:genetics*
chemical_list: D016875:tau Proteins; D006493:Heparin; D004247:DNA