FTDP-17 mutations N279K and S305N in tau produce increased splicing of exon 10

Missense mutations and intronic mutations in the tau gene cause frontotempo ral dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Known miss ense mutations reduce the ability of tau to promote microtubule assembly. I ntronic mutations lead to increased mRNA splicing of the alternatively spli ced exon 10, resulting in an overproduction of tau isoforms with four micro tubule-binding repeats. We show here that the recently identified FTDP-17 m issense mutations N279K and S305N do not reduce the ability of tau to promo te microtubule assembly. Instead they lead to increased splicing of exon 10 , like the intronic mutations. The N279K and S305N mutations define a class of missense mutations in tau whose primary effects are at the RNA level. ( C) 1999 Federation of European Biochemical Societies.