Instability of the octarepeat region of the human prion protein gene.
Instability of the octarepeat region of the human prion protein gene.
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DOI：
10.1371/journal.pone.0026635
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Kong Q
中科院分区：
文献类型：
--
作者：
Li B;Qing L;Yan J;Kong Q
朊病毒病是一种影响人类和许多动物的独特的致命性传染性神经退行性疾病。散发性克雅氏病（sCJD）是人类最常见的朊病毒病，占所有人类朊病毒病例的85-90%，并表现出高度的表型多样性。sCJD的病因仍有待阐明。人朊病毒蛋白基因具有八肽重复区（octapeptide repeats），其通常含有5个24-27 bp的重复（1个九肽和4个八肽编码序列）。八重复序列数增加到6个或更多或减少到3个与人类具有异质表型的遗传性朊病毒疾病有关。在这里，我们报告说，人类octarepeat区域是倾向于收缩或扩张时，在体外进行PCR扩增使用Taq或Pwo聚合酶，并在野生型E。coli细胞。八重复插入突变体甚至更不稳定，并且当在DNA错配修复缺陷的大肠杆菌细胞中复制时，野生型八重复的突变率要高得多。所有观察到的由大肠杆菌中DNA复制产生的八重复突变体都包含在头对头质粒二聚体和DNA折叠分析中（http：mfold.rna.albany.edu/? q= m倍/DNA-折叠-形式）表明八重复区的两条DNA链可能形成多个稳定的发夹结构，表明八重复序列可能在DNA复制或修复过程中形成稳定的发夹结构，从而导致八重复不稳定性。这些结果提供了支持基于体细胞八重复序列突变的人类sCJD病因学模型的第一个证据：1）八重复序列区域的不稳定性导致发育和衰老期间脑细胞中体细胞八重复序列突变的积累，2）这种不稳定性通过衰老细胞中受损的DNA错配修复而增强，和3）最终，一些含有八重复序列突变的脑细胞开始自发从头朊病毒形成和复制，从而引发sCJD。
Prion diseases are a family of unique fatal transmissible neurodegenerative diseases that affect humans and many animals. Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common prion disease in humans, accounting for 85–90% of all human prion cases, and exhibits a high degree of diversity in phenotypes. The etiology of sCJD remains to be elucidated. The human prion protein gene has an octapeptide repeat region (octarepeats) that normally contains 5 repeats of 24–27 bp (1 nonapeptide and 4 octapeptide coding sequences). An increase of the octarepeat numbers to six or more or a decrease of the octarepeat number to three is linked to genetic prion diseases with heterogeneous phenotypes in humans. Here we report that the human octarepeat region is prone to either contraction or expansion when subjected to PCR amplification in vitro using Taq or Pwo polymerase and when replicated in wild type E. coli cells. Octarepeat insertion mutants were even less stable, and the mutation rate for the wild type octarepeats was much higher when replicated in DNA mismatch repair-deficient E.coli cells. All observed octarepeat mutants resulting from DNA replication in E.coli were contained in head-to-head plasmid dimers and DNA mfold analysis (http://mfold.rna.albany.edu/?q=mfold/DNA-Folding-Form) indicates that both DNA strands of the octarepeat region would likely form multiple stable hairpin structures, suggesting that the octarepeat sequence may form stable hairpin structures during DNA replication or repair to cause octarepeat instability. These results provide the first evidence supporting a somatic octarepeat mutation-based model for human sCJD etiology: 1) the instability of the octarepeat region leads to accumulation of somatic octarepeat mutations in brain cells during development and aging, 2) this instability is augmented by compromised DNA mismatch repair in aged cells, and 3) eventually some of the octarepeat mutation-containing brain cells start spontaneous de novo prion formation and replication to initiate sCJD.
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DOI：
10.1002/ajmg.b.31099
发表时间：
2010-10-01
影响因子：
2.8
作者：
Alzualde, A.;Moreno, F.;Lopez de Munain, A.
通讯作者：
Lopez de Munain, A.
影响因子：
4.7
作者：
Brown, LR;Harris, DA
通讯作者：
Harris, DA
影响因子：
16.2
作者：
DIFIGLIA, M;SAPP, E;ARONIN, N
通讯作者：
ARONIN, N
影响因子：
3.5
作者：
Beck, JA;Poulter, M;Tabrizi, SJ
通讯作者：
Tabrizi, SJ
影响因子：
5.3
作者：
DEROOIJ, KE;GANS, PAMD;DENDUNNEN, JT
通讯作者：
DENDUNNEN, JT