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Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.

机译：tau中的错义和5'-剪接位点突变与遗传性痴呆FTDP-17的关联。

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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.
机译：已经描述了13个家族，这些家族患有常染色体显性遗传的痴呆症，称为额颞叶痴呆和与17号染色​​体（FTDP-17）相关的帕金森氏病，历史上称为皮克氏病。大多数FTDP-17病例显示神经元和/或神经胶质包涵体被微管相关蛋白Tau产生的抗体阳性染色，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基因座定位于染色体17q21.11上的2厘摩区域。 tau基因也位于该区域内。现在，我们已经对FTDP-17家族中的tau进行了测序，并鉴定了三个外显子突变（G272V，P301L和R406W）和外显子10的5'剪接位点的三个突变。剪接位点的突变都破坏了潜在的茎-环结构可能参与了调控exon10的选择性剪接。这将导致更频繁地使用5'剪接位点，并增加包含外显子10的tau转录物的比例。外显子10+ Messenger RNA的增加将增加包含四个微管结合重复序列的Tau的比例，这与神经病理学一致在FTDP-17的多个系列中都有介绍。

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