Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements
Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements
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DOI：
10.1073/pnas.96.10.5598
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发表时间：
1999-05-11
影响因子：
11.1
通讯作者：
Schellenberg, GD
中科院分区：
文献类型：
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作者：
D'Souza, I;Poorkaj, P;Schellenberg, GD
额颞叶痴呆伴帕金森综合征，17号染色体型（FTDP-17）是由tan基因突变引起的，FTDP-17的标志性病变是丝状tan包涵体，Tau突变可能是通过改变蛋白质功能或基因调控致病的，在这里，我们表明错义，沉默，内含子tau突变可通过作用于3种不同的顺式作用调控元件来增加或减少tau外显子10（E10）的剪接。这些元件包括外显子剪接增强子，其可以被加强（突变（N）279（K））或被破坏（突变Delta 280（K）），导致组成型E10包含或从tau转录物中排除E10。E10含有第二个调控元件，即外显子剪接沉默子，其功能被沉默FTDP-17突变（（L）284（L））消除，导致过量E10包含。抑制E10剪接的第三个元件包含在E10的5'剪接位点直接侧翼的内含子序列中，并且该元件中的内含子FTDP-17突变增强E10包含。因此，tau突变通过多种病理机制引起FTDP-17，这可以解释在FTDP-17中观察到的表型异质性，如本文描述的具有tau病理学以及淀粉样蛋白和神经炎斑块的不寻常家族所例示的。
Frontotemporal dementia with parkinsonism, chromosome 17 type (FTDP-17) is caused by mutations in the tan gene, and the signature lesions of FTDP-17 are filamentous tan 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 decrease 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 strengthened (mutation (N)279(K)) or destroyed (mutation Delta 280(K)), resulting in either constitutive E10 inclusion or the exclusion of E10 from tau transcripts. E10 contains a second regulatory element that is an exon splicing silencer, the function of which is abolished by a silent FTDP-17 mutation ((L)284(L)), resulting in excess E10 inclusion. A third element inhibiting E10 splicing is contained in the intronic sequences directly flanking the 5' splice site of E10 and intronic FTDP-17 mutations in this element enhance E10 inclusion. Thus, tau mutations cause FTDP-17 by multiple pathological mechanisms, which may explain the phenotypic heterogeneity observed in FTDP-17, as exemplified by an unusual family described here with tau pathology as well as amyloid and neuritic plaques.