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

摘要

Frontotemporal dementia with parkinsonism, chroniosome 17 type (FTDP-I7) is caused by mutations in the tau gene, and the signature lesions of FTDP-17 are filamentous tau inclusions. Tau mutations may be pathogenic either by altering protein function or gene regulation. Here we show that missense, silent, and intronic tau mutations can increase or decrcase splicing of tau exon 10 (E10) by acting on 3 different cis-acting regulatory elements. These elements include an exon splicing enhancer that can either be strength- ened (mutation x279k) or destroyed (mutation delta A280k), resulting in either constitutive EIO inclusion or the exclusion of E10 from tau transcripts. EIO contains a second regulatory element that is an exon splicing silencer, the function of which is abolished by a silent FTDP-17 mutation (L284L), resulting in excess E10 inclusion. A third element inhibiting E10 splicing is contained in the intronic sequences directly flanking the 5' splice site of FIO and intronic FTDP-17 mutations in this element enhance E10 inclusion.