...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Journal of Molecular and Cellular Cardiology >Inhibition of nonsense-mediated mRNA decay by antisense morpholino oligonucleotides restores functional expression of hERG nonsense and frameshift mutations in long-QT syndrome.
【24h】

Inhibition of nonsense-mediated mRNA decay by antisense morpholino oligonucleotides restores functional expression of hERG nonsense and frameshift mutations in long-QT syndrome.

机译：反义吗啉代寡核苷酸抑制无意义介导的mRNA衰变可恢复长QT综合征中hERG无意义和移码突变的功能性表达。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Mutations in the human ether-a-go-go-related gene (hERG) cause long-QT syndrome type 2 (LQT2). We previously described a homozygous LQT2 nonsense mutation Q1070X in which the mutant mRNA is degraded by nonsense-mediated mRNA decay (NMD) leading to a severe clinical phenotype. The degradation of the Q1070X transcript precludes the expression of truncated but functional mutant channels. In the present study, we tested the hypothesis that inhibition of NMD can restore functional expression of LQT2 mutations that are targeted by NMD. We showed that inhibition of NMD by RNA interference-mediated knockdown of UPF1 increased Q1070X mutant channel protein expression and hERG current amplitude. More importantly, we found that specific inhibition of downstream intron splicing by antisense morpholino oligonucleotides prevented NMD of the Q1070X mutant mRNA and restored the expression of functional Q1070X mutant channels. The restoration of functional expression by antisense morpholino oligonucleotides was also observed in LQT2 frameshift mutations. Our findings suggest that inhibition of NMD by antisense morpholino oligonucleotides may be a potential therapeutic approach for some LQT2 patients carrying nonsense and frameshift mutations.
机译：人与人在一起的醚相关基因（hERG）中的突变会导致长QT综合征2型（LQT2）。我们先前描述了纯合LQT2无意义突变Q1070X，其中突变mRNA被无意义介导的mRNA衰变（NMD）降解，导致严重的临床表型。 Q1070X转录本的降解排除了截短但功能正常的突变体通道的表达。在本研究中，我们测试了以下假设：抑制NMD可以恢复NMD靶向的LQT2突变的功能性表达。我们表明，RNA干扰介导的UPF1敲低对NMD的抑制作用会增加Q1070X突变体通道蛋白的表达和hERG电流幅度。更重要的是，我们发现反义吗啉代寡核苷酸对下游内含子剪接的特异性抑制可防止Q1070X突变体mRNA的NMD并恢复功能性Q1070X突变体通道的表达。在LQT2移码突变中也观察到反义吗啉代寡核苷酸恢复功能表达。我们的发现表明，反义吗啉代寡核苷酸对NMD的抑制可能是一些携带无义和移码突变的LQT2患者的潜在治疗方法。

著录项

相似文献

  • 外文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号