Lippa C F, Zhukareva V, Kawarai T, Uryu K, Shafiq M, Nee L E, Grafman J, Liang Y, St George-Hyslop P H, Trojanowski J Q, Lee V M
Department of Neurology, Medical College of Pennsylvania- Hahnemann University, Philadelphia 19129, USA.
Ann Neurol. 2000 Dec;48(6):850-8.
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.
目前尚不清楚tau基因突变如何导致与17号染色体相关的额颞叶痴呆伴帕金森综合征（FTDP - 17），但外显子10（E10）或其下游内含子中的突变可能通过改变E10剪接、扰乱正常的四微管结合重复tau与三微管结合重复tau 1:1比例（4R:3R tau比例）并形成tau包涵体而具有致病性。我们报告了一名55岁患有额颞叶痴呆且有FTDP - 17家族史的女性，我们在她身上发现了一种新的E12（Glu342Val）tau基因突变、显著的额颞叶神经元丢失、胞浆内tau聚集、双螺旋tau细丝、4R tau信使核糖核酸增加、无E2或E3插入的4R tau增加、有这些插入的4R tau减少以及灰质和白质中4R:3R tau比例大于1。因此，这种新的Glu342Val突变可能通过前所未有的机制导致FTDP - 17，这些机制改变E2、E3和E10的剪接，优先增加无氨基末端插入的4R tau，并促进tau细丝聚集成细胞病变包涵体。
