無義突變

無義突變（Nonsense mutation）是基因序列中造成終止密碼子提早出現的點突變，會使轉譯提前終止，產生大小較小、不具功能的蛋白質產物^[1]，無義突變發生的位點距正常的終止密碼子越近，對蛋白質造成的影響一般越小^[2]。杜興氏肌肉營養不良症、某些乙型地中海貧血（英语：Beta thalassemia）、少數囊腫性纖維化（G542X）、胡勒尔综合征（英语：Hurler syndrome）與嬰兒嚴重肌陣攣性癲癇等遺傳性疾病和數種癌症均為重要的基因發生無義突變造成^[3]^[4]，有統計顯示造成人類疾病的突變中有5%至15%為無義突變^[5]。

細胞轉譯具無義突變的mRNA時會啟動無義介導的mRNA降解（NMD）途徑抑制轉譯，並將mRNA降解移除^[6]。某些情況下細胞中的無義突變抑制因子（如突變的tRNA）會抑制無義突變，使核糖體轉譯至突變位點時發生轉譯連讀（translational readthrough）而繼續轉譯^[7]。氨基糖苷類化合物可與rRNA中負責解讀密碼子的區域結合，降低tRNA配對的準確度，因而有促進轉譯連讀的效果，可能用作治療無義突變所致遺傳疾病之藥物^[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

假設上述基因序列中，編碼精氨酸的密碼子CGA發生無義突變而變為TGA，將使轉譯提前終止，產生較小的蛋白質。

    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

參考文獻

^ 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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