无义突变

无义突变（Nonsense mutation）是基因序列中造成终止密码子提早出现的点突变，会使翻译提前终止，产生大小较小、不具功能的蛋白质产物^[1]，无义突变发生的位点距正常的终止密码子越近，对蛋白质造成的影响一般越小^[2]。杜兴氏肌肉营养不良症、某些乙型地中海贫血（英语：Beta thalassemia）、少数囊肿性纤维化（G542X）、胡勒尔综合征（英语：Hurler syndrome）与婴儿严重肌阵挛性癫痫等遗传性疾病和数种癌症均为重要的基因发生无义突变造成^[3]^[4]，有统计显示造成人类疾病的突变中有5%至15%为无义突变^[5]。

细胞翻译具无义突变的mRNA时会启动无义介导的mRNA降解（NMD）途径抑制翻译，并将mRNA降解移除^[6]。某些情况下细胞中的无义突变抑制因子（如突变的tRNA）会抑制无义突变，使核糖体翻译至突变位点时发生翻译连读（translational readthrough）而继续翻译^[7]。氨基糖苷类化合物可与rRNA中负责解读密码子的区域结合，降低tRNA配对的准确度，因而有促进翻译连读的效果，可能用作治疗无义突变所致遗传疾病之药物^[3]。

案例

    DNA: 5' - ATG ACT CAC CGA GCG CGA AGC TGA - 3'
         3' - TAC TGA GTG GCT CGC GCT TCG ACT - 5'
   mRNA: 5' - AUG ACU CAC CGA GCG CGA AGC UGA - 3'
   蛋白質:     Met Thr His Arg Ala Arg Ser 終止

假设上述基因序列中，编码精氨酸的密码子CGA发生无义突变而变为TGA，将使翻译提前终止，产生较小的蛋白质。

    DNA: 5' - ATG ACT CAC TGA GCG CGA AGC TGA - 3'
         3' - TAC TGA GTG ACT CGC GCT TCG ACT - 5'
   mRNA: 5' - AUG ACU CAC UGA GCG CGU AGC UGA - 3'
   蛋白質:     Met Thr His 終止

参考文献

^ Sharma, Jyoti; Keeling, Kim M.; Rowe, Steven M. Pharmacological approaches for targeting cystic fibrosis nonsense mutations. European Journal of Medicinal Chemistry. 2020-08-15, 200: 112436. ISSN 0223-5234. PMC 7384597  . PMID 32512483. doi:10.1016/j.ejmech.2020.112436 （英语）.
^ Balasubramanian, Suganthi; Fu, Yao; Pawashe, Mayur; McGillivray, Patrick; Jin, Mike; Liu, Jeremy; Karczewski, Konrad J.; MacArthur, Daniel G.; Gerstein, Mark. Using ALoFT to determine the impact of putative loss-of-function variants in protein-coding genes. Nature Communications. 2017-08-29, 8 (1): 382. Bibcode:2017NatCo...8..382B. ISSN 2041-1723. PMC 5575292  . PMID 28851873. doi:10.1038/s41467-017-00443-5 （英语）.
^ ^3.0 ^3.1 Kim M. Keeling, Ming Du, and David M Bedwell. Therapies of Nonsense-Associated Diseases. [2021-05-04]. （原始内容存档于2021-11-10） –通过NCBI.
^ Guimbellot, Jennifer; Sharma, Jyoti; Rowe, Steven M. Toward inclusive therapy with CFTR modulators: Progress and challenges. Pediatric Pulmonology. November 2017, 52 (S48): S4–S14. ISSN 1099-0496. PMC 6208153  . PMID 28881097. doi:10.1002/ppul.23773.
^ Fiona Carragher, Mike Champion. Inherited metabolic disease. Clinical Biochemistry: Metabolic and Clinical Aspects (Third Edition). Churchill Livingstone. 2014: 461-483 [2021-05-04]. （原始内容存档于2021-05-06）.
^ Baker, K. E.; Parker, R. Nonsense-mediated mRNA decay: Terminating erroneous gene expression. Current Opinion in Cell Biology. 2004, 16 (3): 293–299. PMID 15145354. doi:10.1016/j.ceb.2004.03.003.
^ David L. Nelson; et al. Principles of Biochemistry (vol. 3). New York, NY: W. H. Freeman and Company. 2013: 1134. ISBN 978-1-4292-3414-6.

[1] Sharma, Jyoti; Keeling, Kim M.; Rowe, Steven M. Pharmacological approaches for targeting cystic fibrosis nonsense mutations. European Journal of Medicinal Chemistry. 2020-08-15, 200: 112436. ISSN 0223-5234. PMC 7384597  . PMID 32512483. doi:10.1016/j.ejmech.2020.112436 （英语）.

[2] Balasubramanian, Suganthi; Fu, Yao; Pawashe, Mayur; McGillivray, Patrick; Jin, Mike; Liu, Jeremy; Karczewski, Konrad J.; MacArthur, Daniel G.; Gerstein, Mark. Using ALoFT to determine the impact of putative loss-of-function variants in protein-coding genes. Nature Communications. 2017-08-29, 8 (1): 382. Bibcode:2017NatCo...8..382B. ISSN 2041-1723. PMC 5575292  . PMID 28851873. doi:10.1038/s41467-017-00443-5 （英语）.

[Keeling-3] 3.0 ^3.1 Kim M. Keeling, Ming Du, and David M Bedwell. Therapies of Nonsense-Associated Diseases. [2021-05-04]. （原始内容存档于2021-11-10） –通过NCBI.

[4] Guimbellot, Jennifer; Sharma, Jyoti; Rowe, Steven M. Toward inclusive therapy with CFTR modulators: Progress and challenges. Pediatric Pulmonology. November 2017, 52 (S48): S4–S14. ISSN 1099-0496. PMC 6208153  . PMID 28881097. doi:10.1002/ppul.23773.

[5] Fiona Carragher, Mike Champion. Inherited metabolic disease. Clinical Biochemistry: Metabolic and Clinical Aspects (Third Edition). Churchill Livingstone. 2014: 461-483 [2021-05-04]. （原始内容存档于2021-05-06）.

[6] Baker, K. E.; Parker, R. Nonsense-mediated mRNA decay: Terminating erroneous gene expression. Current Opinion in Cell Biology. 2004, 16 (3): 293–299. PMID 15145354. doi:10.1016/j.ceb.2004.03.003.

[7] David L. Nelson; et al. Principles of Biochemistry (vol. 3). New York, NY: W. H. Freeman and Company. 2013: 1134. ISBN 978-1-4292-3414-6.

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