Nonsense-mediated mRNA decay: inter-individual variability and human disease.
Nonsense-mediated mRNA decay: inter-individual variability and human disease.
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DOI：
10.1016/j.neubiorev.2013.10.016
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发表时间：
2014-10
影响因子：
8.2
通讯作者：
Gecz, Jozef
中科院分区：
文献类型：
--
作者：
Lam Son Nguyen;Wilkinson, Miles F.;Gecz, Jozef
关键词：
无义介导的mRNA衰变（NMD）是一种调控途径，其功能是降解含有提前终止密码子（PTC）的转录物并维持正常的转录组稳态。产生PTC的无义突变和移码突变导致大约三分之一的已知人类遗传疾病，因此NMD在人类疾病中具有潜在的重要作用。在受影响的基因携带PTC产生突变的遗传性疾病中，NMD就像一把双刃剑。虽然它可以通过降解编码有害的显性阴性截短蛋白的含PTC的mRNA而使患者受益，但当编码突变但仍有功能的蛋白的含PTC的mRNA被降解时，它也可以使疾病恶化。有证据表明，NMD的大小在个体之间是不同的，这反过来又被证明与临床表现和患者对促进PTC通读的药物的反应相关。在这篇综述中，我们研究的证据支持存在个体间变异的NMD效率和讨论的遗传因素，这种变异性的基础。我们建议，NMD效率的个体间变异是人类群体中的一种常见现象，并且在测试、开发和做出针对由携带PTC的基因引起的疾病的治疗决策时，应考虑个体的NMD效率。
Nonsense-Mediated mRNA Decay (NMD) is a regulatory pathway that functions to degrade transcripts containing premature termination codons (PTCs) and to maintain normal transcriptome homeostasis. Nonsense and frameshift mutations that generate PTCs cause approximately one-third of all known human genetic diseases and thus NMD has a potentially important role in human disease. In genetic disorders in which the affected genes carry PTC-generating mutations, NMD acts as a double-edge sword. While it can benefit the patient by degrading PTC-containing mRNAs that encode detrimental, dominant-negative truncated proteins, it can also make the disease worse when a PTC-containing mRNA is degraded that encodes a mutant but still functional protein. There is evidence that the magnitude of NMD varies between individuals, which, in turn, has been shown to correlate with both clinical presentations and the patients’ responses to drugs that promote read-through of PTCs. In this review, we examine the evidence supporting the existence of inter-individual variability in NMD efficiency and discuss the genetic factors that underlie this variability. We propose that inter-individual variability in NMD efficiency is a common phenomenon in human populations and that an individual’s NMD efficiency should be taken into consideration when testing, developing, and making therapeutic decisions for diseases caused by genes harboring PTCs.
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DOI：
10.1158/1541-7786.mcr-09-0502
发表时间：
2010-03
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Gardner LB
通讯作者：
Gardner LB
影响因子：
4.8
作者：
Denning, G;Jamieson, L;Fields, AP
通讯作者：
Fields, AP
影响因子：
14.9
作者：
Applequist, SE;Selg, M;Jack, HM
通讯作者：
Jack, HM
影响因子：
4.5
作者：
Chiu, SY;Serin, G;Maquat, LE
通讯作者：
Maquat, LE
影响因子：
4.8
作者：
Degot, S;Le Hir, H;Tomasetto, C
通讯作者：
Tomasetto, C