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Mayo Clinic Jacksonville, Florida 32224, USA.
Nature. 1998 Jun 18;393(6686):702-5. doi: 10.1038/31508.
Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Pick's disease. Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics. Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q21.11; the tau gene also lies within this region. We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon 10. The splice-site mutations all destabilize a potential stem-loop structure which is probably involved in regulating the alternative splicing of exon10. This causes more frequent usage of the 5' splice site and an increased proportion of tau transcripts that include exon 10. The increase in exon 10+ messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17.
已经描述了13个家族患有一种常染色体显性遗传的痴呆症，名为与17号染色体相关的额颞叶痴呆和帕金森症（FTDP-17），历史上称为匹克氏病。大多数FTDP-17病例显示神经元和/或神经胶质包涵体，用针对微管相关蛋白Tau产生的抗体染色呈阳性，尽管Tau病理在数量（或严重程度）和特征上有很大差异。先前的研究已将FTDP-17基因座定位到17q21.11染色体上的一个2厘摩区域；tau基因也位于该区域内。我们现在对FTDP-17家族中的tau进行了测序，鉴定出三个错义突变（G272V、P301L和R406W）以及外显子10的5'剪接位点的三个突变。剪接位点突变均破坏了一个可能参与调节外显子10可变剪接的潜在茎环结构。这导致5'剪接位点的使用频率增加，并且包含外显子10的tau转录本比例增加。外显子10+信使RNA的增加将增加含有四个微管结合重复序列的Tau的比例，这与几个FTDP-17家族中描述的神经病理学一致。
