It is unclear how tau gene mutations cause frontotemporal dementia (FTD) with parkinsonism linked to chromosome 17 (FTDP-17), but those in exon 10 (E10) or the following intron may be pathogenic by altering E10 splicing, perturbing the normal 1:1 ratio of four versus three microtubule-binding repeat tau (4R:3R tau ratio) and forming tau inclusions. We report on a 55-year old woman with frontotemporal dementia and a family history of FTDP-17 in whom we found a novel E12 (Glu342Val) tau gene mutation, prominent frontotemporal neuron loss, intracytoplasmic tau aggregates, paired helical tau filaments, increased 4R tau messenger RNA, increased 4R tau without E2 or E3 inserts, decreased 4R tau with these inserts, and a 4R:3R tau ratio greater than 1 in gray and white matter. Thus, this novel Glu342Val mutation may cause FTDP-17 by unprecedented mechanisms that alter splicing of E2, E3, and E10 to preferentially increase 4R tau without amino terminal inserts and promote aggregation of tau filaments into cytopathic inclusions.

译文

目前尚不清楚tau基因突变如何导致与17号染色体 (FTDP-17) 相关的帕金森综合征的额颞叶痴呆 (FTD),但外显子10 (E10) 或以下内含子中的突变可能通过改变E10剪接而致病,扰动四个与三个微管结合重复重复tau的正常1:1比 (4R:3R tau比) 并形成tau内含物。我们报道了一名55岁的患有额颞叶痴呆和FTDP-17家族史的女性,我们发现了新的E12 (Glu342Val) tau基因突变,突出的额颞叶神经元丢失,胞浆内tau聚集体,成对的螺旋tau细丝,增加的4R tau信使RNA,没有E2或E3插入物的4R tau增加,使用这些插入物的4R tau降低,灰色和白色物质的4R:3R tau比大于1。因此,这种新的Glu342Val突变可能通过前所未有的机制引起FTDP-17,这些机制改变E2、E3和E10的剪接,以优先增加没有氨基末端插入物的4rtau,并促进tau丝聚集到细胞病变内含物中。

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