C9ORF72 GGGGCC Expanded Repeats Produce Splicing Dysregulation which Correlates with Disease Severity in Amyotrophic Lateral Sclerosis.
C9ORF72 GGGGCC Expanded Repeats Produce Splicing Dysregulation which Correlates with Disease Severity in Amyotrophic Lateral Sclerosis.
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DOI：
10.1371/journal.pone.0127376
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Shaw PJ
中科院分区：
文献类型：
--
作者：
Cooper-Knock J;Bury JJ;Heath PR;Wyles M;Higginbottom A;Gelsthorpe C;Highley JR;Hautbergue G;Rattray M;Kirby J;Shaw PJ
C9 ORF 72的内含子GGGGCC重复扩增是肌萎缩侧索硬化症（ALS）和额颞叶痴呆症最常见的遗传变异。神经退行性变的机制尚不清楚，但已经提出了由重复序列转录的RNA灶介导的对RNA加工的直接影响。基因表达谱分析利用从来自人ALS患者的运动神经元和淋巴母细胞样细胞系提取的总RNA，包括具有C9 ORF 72扩增的那些，和对照。在淋巴母细胞系中，还检查了扩增长度和有义和反义RNA病灶的频率。基因水平分析揭示了一些差异表达的网络和两种细胞类型表现出失调的网络功能丰富的基因编码的“RNA剪接”蛋白。这些基因与独立产生的GGGGCC重复蛋白结合伴侣的列表有显著重叠。在外显子水平，在源自C9 ORF 72-ALS患者的淋巴母细胞中，剪接一致性低于源自非C9 ORF 72 ALS患者或对照的细胞系;此外，在源自疾病进展较快的患者的样品中，剪接一致性较低。有义RNA灶的频率显示出在来自生存期较短的患者的淋巴母细胞中较高的趋势，但疾病严重程度和DNA扩增长度之间没有可检测的相关性。编码C9 ORF 72扩增的预测结合伴侣的基因的上调与这些蛋白的螯合的尝试补偿一致。许多研究分析了C9 ORF 72扩增引起的转录组变化，但迄今为止的结果不一致。作为一个潜在的解释，我们认为，动态螯合的RNA加工蛋白质的RNA焦点可能会导致剪接的一致性损失，事实上，在我们的样本测量剪接的一致性与疾病的严重程度。
An intronic GGGGCC-repeat expansion of C9ORF72 is the most common genetic variant of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The mechanism of neurodegeneration is unknown, but a direct effect on RNA processing mediated by RNA foci transcribed from the repeat sequence has been proposed. Gene expression profiling utilised total RNA extracted from motor neurons and lymphoblastoid cell lines derived from human ALS patients, including those with an expansion of C9ORF72, and controls. In lymphoblastoid cell lines, expansion length and the frequency of sense and antisense RNA foci was also examined. Gene level analysis revealed a number of differentially expressed networks and both cell types exhibited dysregulation of a network functionally enriched for genes encoding ‘RNA splicing’ proteins. There was a significant overlap of these genes with an independently generated list of GGGGCC-repeat protein binding partners. At the exon level, in lymphoblastoid cells derived from C9ORF72-ALS patients splicing consistency was lower than in lines derived from non-C9ORF72 ALS patients or controls; furthermore splicing consistency was lower in samples derived from patients with faster disease progression. Frequency of sense RNA foci showed a trend towards being higher in lymphoblastoid cells derived from patients with shorter survival, but there was no detectable correlation between disease severity and DNA expansion length. Up-regulation of genes encoding predicted binding partners of the C9ORF72 expansion is consistent with an attempted compensation for sequestration of these proteins. A number of studies have analysed changes in the transcriptome caused by C9ORF72 expansion, but to date findings have been inconsistent. As a potential explanation we suggest that dynamic sequestration of RNA processing proteins by RNA foci might lead to a loss of splicing consistency; indeed in our samples measurement of splicing consistency correlates with disease severity.
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影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
影响因子：
16.2
作者：
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DOI：
10.1093/brain/awu120
发表时间：
2014-07
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
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通讯作者：
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影响因子：
12.7
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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