Tau gene mutation in familial progressive subcortical gliosis

Familial forms of frontotemporal dementias are associated with mutations in the tau gene. A kindred affected by progressive subcortical gliosis (PSG), a rare form of presenile dementia, has genetic linkage to chromosome 17q21 -22 (refs. 1-3). This kindred (PSG-1) is included in the 'frontotemporal de mentias and Parkinsonism linked to chromosome 17' group along with kindreds affected by apparently different forms of atypical dementias(4). Some of t hese kindreds have mutations in the tau gene(5-10). We report here that PSC -1 has a tau mutation at position +16 of the intron after exon 10. The muta tion destabilizes a predicted stem-loop structure and leads to an over-repr esentation of the soluble four-repeat tau isoforms, which assemble into wid e, twisted, ribbon-like filaments and ultimately result in abundant neurona l and glial tau pathology. The mutations associated with PSC and other atyp ical dementias can be subdivided into three groups according to their tau g ene locations and effects on tau. The existence of tau mutations with disti nct pathogenetic mechanisms may explain the phenotypic heterogeneity of aty pical dementias that previously led to their classification into separate d isease entities.