School of Biological Sciences, University of East Anglia, Norwich, UK.
Hum Mol Genet. 2012 Feb 15;21(4):852-62. doi: 10.1093/hmg/ddr515. Epub 2011 Nov 6.
Myotonic dystrophy (DM) is caused by a triplet repeat expansion in the non-coding region of either the DMPK (DM1) or CNBP (DM2) gene. Transcription of the expanded region causes accumulation of double-stranded RNA (dsRNA) in DM cells. We sought to determine how expression of triplet repeat RNA causes the varied phenotype typical of DM. Global transcription was measured in DM and non-DM cataract samples using Illumina Bead Arrays. DM samples were compared with non-DM samples and lists of differentially expressed genes (P≤ 0.05) were prepared. Gene set enrichment analysis and the Interferome database were used to search for significant patterns of gene expression in DM cells. Expression of individual genes was measured using quantitative real-time polymerase chain reaction. DMPK and CNBP expression was confirmed in native lens cells showing that a toxic RNA gain of function mechanism could exist in lens. A high proportion, 83% in DM1 and 75% in DM2, of the significantly disregulated genes were shared by both forms of the disease, suggesting a common mechanism. The upregulated genes in DM1 and DM2 were highly enriched in both interferon-regulated genes (IRGs) and genes associated with the response to dsRNA and the innate immune response. The characteristic fingerprint of IRGs and the signalling pathways identified in lens cells support a role for dsRNA activation of the innate immune response in the pathology of DM. This new evidence forms the basis for a novel hypothesis to explain the complex mechanism of DM.
肌强直性营养不良（DM）是由 DMPK（DM1）或 CNBP（DM2）基因非编码区的三核苷酸重复扩展引起的。扩展区域的转录导致 DM 细胞中双链 RNA（dsRNA）的积累。我们试图确定三核苷酸重复 RNA 的表达如何导致 DM 的典型多变表型。使用 Illumina Bead Arrays 测量 DM 和非 DM 白内障样本中的全局转录。将 DM 样本与非 DM 样本进行比较，并准备差异表达基因列表（P≤0.05）。使用基因集富集分析和 Interferome 数据库搜索 DM 细胞中显著的基因表达模式。使用定量实时聚合酶链反应测量个别基因的表达。在表现出毒性 RNA 获得功能机制的天然晶状体细胞中证实了 DMPK 和 CNBP 的表达，这表明这种机制可能存在于晶状体中。两种形式的疾病都有 83%的显著失调基因（DM1）和 75%的显著失调基因（DM2）共享，这表明存在共同的机制。DM1 和 DM2 中上调的基因在干扰素调节基因（IRGs）和与 dsRNA 反应以及先天免疫反应相关的基因中高度富集。IRGs 和在晶状体细胞中鉴定出的信号通路的特征指纹支持 dsRNA 激活先天免疫反应在 DM 病理学中的作用。这一新证据为解释 DM 复杂机制的新假设奠定了基础。
