Recently, a series of both non-coding (intronic) and coding (exonic) mutati
ons in the tau gene have been linked to a family of autosomal dominant deme
ntias referred to as frontotemporal dementia-17. While linkage analysis has
demonstrated that these mutations segregate with disease in affected famil
ies, it is unclear how mutant tau proteins could lead to the degenerative c
ascade seen in frontotemporal dementia-17. The present study demonstrates t
hat coding mutations of tau seen in frontotemporal dementia-17 exhibit alte
red physical and structural characteristics as determined by reverse phase
high performance liquid chromatography and circular dichroism spectroscopy.
These data suggest that the previously identified mutations in the tau gen
e seen in frontotemporal dementia-17 are not merely benign polymorphisms, b
ut may have functional consequences for microtubule binding, microtubule po
lymerization, and the abnormal aggregation of tau seen in a variety of neur
odegenerative diseases. (C) 1999 Elsevier Science Ireland Ltd. All rights r
eserved.