MUTATIONS TO NONSENSE CODONS IN HUMAN GENETIC-DISEASE - IMPLICATIONS FOR GENE-THERAPY BY NONSENSE SUPPRESSOR TRANSFER-RNAS
MUTATIONS TO NONSENSE CODONS IN HUMAN GENETIC-DISEASE - IMPLICATIONS FOR GENE-THERAPY BY NONSENSE SUPPRESSOR TRANSFER-RNAS
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DOI：
10.1093/nar/22.8.1327
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发表时间：
1994-04-25
影响因子：
14.9
通讯作者：
MARTIN, R
中科院分区：
文献类型：
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作者：
ATKINSON, J;MARTIN, R
无义抑制 tRNA 已被建议作为人类体细胞基因治疗的潜在药物。该实验室最近的工作描述了 3' 密码子上下文对人类无义抑制子效率的显着影响。由无义密码子引起的人类疾病的报告数量迅速增加，促使我们确定 UAG、UAA 或 UGA 密码子的突变谱及其各自的 3' 上下文如何影响用于基因治疗目的的人类抑制 tRNA 的效率。本文对导致人类种系或躯体疾病的 179 个无义密码子突变事件进行了调查。分析显示，UAA、UAG 和 UGA 的突变比例分别约为 1:2:3。这种模式与天然存在的终止密码子的模式相似，但不相同。还分析了要停止的新突变的 3' 背景。该模式再次与自然终止信号周围的环境相似。这些结果意味着无义突变和天然终止密码子对无义抑制 tRNA 抑制的敏感性几乎没有差异。对无义突变改变的密码子的分析表明，设计带有 Trp、Gin 和 Glu 的人类 UAG 抑制 tRNA 的努力；带有 Gin 和 Glu 的 UAA 抑制剂，以及插入 Arg 的 UGA 抑制剂，将是开发抑制 tRNA 作为人类体细胞基因治疗药物的重要一步。
Nonsense suppressor tRNAs have been suggested as potential agents for human somatic gene therapy. Recent work from this laboratory has described significant effects of 3' codon context on the efficiency of human nonsense suppressors. A rapid increase in the number of reports of human diseases caused by nonsense codons, prompted us to determine how the spectrum of mutation to either UAG, UAA or UGA codons and their respective 3' contexts, might effect the efficiency of human suppressor tRNAs employed for purposes of gene therapy. This paper presents a survey of 179 events of mutations to nonsense codons which cause human germline or somatic disease. The analysis revealed a ratio of approximately 1:2:3 for mutation to UAA, UAG and UGA respectively. This pattern is similar, but not identical, to that of naturally occurring stop codons. The 3' contexts of new mutations to stop were also analysed. Once again, the pattern was similar to the contexts surrounding natural termination signals. These results imply there will be little difference in the sensitivity of nonsense mutations and natural stop codons to suppression by nonsense suppressor tRNAs. Analysis of the codons altered by nonsense mutations suggests that efforts to design human UAG suppressor tRNAs charged with Trp, Gin, and Glu; UAA suppressors charged with Gin and Glu, and UGA suppressors which insert Arg, would be an essential step in the development,of suppressor tRNAs as agents of human somatic gene therapy.