Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements

Frontotemporal dementia with parkinsonism, chromosome 17 type (FTDP-17) is caused by mutations in the tan gene, and the signature lesions of FTDP-17 a re filamentous tan inclusions, Tau mutations may be pathogenic either by al tering protein function or gene regulation, Here we show that missense, sil ent, and intronic tau mutations can increase or decrease splicing of tau ex on 10 (E10) by acting on 3 different cis-acting regulatory elements. These elements include an exon splicing enhancer that can either be strengthened (mutation (N)279(K)) or destroyed (mutation Delta 280(K)), resulting in eit her constitutive E10 inclusion or the exclusion of E10 from tau transcripts . E10 contains a second regulatory element that is an exon splicing silence r, the function of which is abolished by a silent FTDP-17 mutation ((L)284( L)), resulting in excess E10 inclusion. A third element inhibiting E10 spli cing is contained in the intronic sequences directly flanking the 5' splice site of E10 and intronic FTDP-17 mutations in this element enhance E10 inc lusion. Thus, tau mutations cause FTDP-17 by multiple pathological mechanis ms, which may explain the phenotypic heterogeneity observed in FTDP-17, as exemplified by an unusual family described here with tau pathology as well as amyloid and neuritic plaques.