A novel tau mutation in exon 9 (1260V) causes a four-repeat tauopathy.
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.
Grover
Andrew
A
Laboratory of Neurogenetics, Neuroscience Department, Mayo Clinic, Jacksonville, FL 32224, USA.
England
Elisabet
E
Baker
Mathew
M
Sahara
Naruhiko
N
Adamson
Jennifer
J
Granger
Brian
B
Houlden
Henry
H
Passant
Ulla
U
Yen
Shu-Hui
SH
DeTure
Michael
M
Hutton
Michael
M
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*
D016875:tau Proteins; D006493:Heparin; D004247:DNA