Tau gene mutation K257T causes a tauopathy similar to Pick's disease.

Exonic and intronic mutations in Tau cause neurodegenerative syndromes characterized by frontotemporal dementia and filamentous tau protein deposits. Here we describe a K257T missense mutation in exon 9 of Tau. The proband, a 47-yr-old male, presented with severe personality changes followed by semantic memory loss. A diagnosis of Pick's disease was made. The symptoms progressed until death at age 51. The proband's brain showed a marked frontotemporal atrophy that was most pronounced in the temporal lobes. Numerous tau-immunoreactive Pick bodies were present in the neocortex and the hippocampal formation, as well as in some subcortical brain regions. Their appearance and staining characteristics were indistinguishable from those of sporadic Pick's disease. Diffuse staining for hyperphosphorylated tau was also observed in some nerve cell bodies. Immunoblot analysis of sarkosyl-insoluble tau showed 2 major bands of 60 and 64 kDa and 2 very minor bands of 68 and 72 kDa. Upon dephosphorylation, these bands resolved into 6 bands consisting of 3-repeat and 4-repeat tau isoforms, with an overall preponderance of 3-repeat tau. Isolated tau filaments were narrow, irregularly twisted ribbons. Biochemically, recombinant tau proteins with the K257T mutation showed a reduced ability to promote microtubule assembly, suggesting that this may be the primary effect of the mutation. In addition, the K257T mutation was found to stimulate heparin-induced assembly of 3-repeat tau into filaments. Taken together, the present findings indicate that the K257T mutation in Tau can cause a dementing condition similar to Pick's disease.