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Pick's disease is associated with mutations in the tau gene
Author(s) -
PickeringBrown Stuart,
Baker Matt,
Yen ShuHui,
Liu WanKyng,
Hasegawa Masato,
Cairns Nigel,
Lantos Peter L.,
Rossor Martin,
Iwatsubo Takeshi,
Davies Yvonne,
Allsop David,
Furlong Rob,
Owen Frank,
Hardy John,
Mann David,
Hutton Mike
Publication year - 2000
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 - 10.1002/1531-8249(200012)48:6<859::aid-ana6>3.0.co;2-1
Subject(s) - frontotemporal dementia , genetics , mutation , gene , biology , missense mutation , tau protein , gene mutation , dementia , disease , alzheimer's disease , medicine , pathology
Recently, mutations within the tau gene have been associated with some familial forms of frontotemporal dementia. To investigate whether tau gene mutations are also associated with Pick's disease, we analyzed the tau gene in 30 cases of pathologically confirmed Pick's disease. Two coding mutations were identified in separate cases of Pick's disease. A glycine‐to‐arginine mutation at codon 389 was detected in 1 case and a lysine‐to‐threonine mutation at codon 257 was identified in another. Analysis of dephosphorylated tau from the brain of the patient with the codon 389 mutation revealed a prominent band representing tau, with four microtubule‐binding domains and no amino terminal inserts. This is in contrast to Pick's disease without any tau gene mutations, which consist of tau with mainly three microtubule‐binding domains and only a trace of tau, with four microtubule‐binding domains. Functional analysis of tau with these two mutations demonstrated a reduced ability of tau to promote microtubule assembly. Surprisingly, these mutations increased tau's susceptibility to calpain I digestion, suggesting that this feature may be related to the formation of a Pick type of histology. Moreover, these data suggest that Pick's disease is not a separate entity but part of the frontotemporal dementia disease spectrum. Ann Neurol 2000;48:859–867