錯義突變

在遺傳學，錯義突變是一種點突變，其中單個核苷酸變化導致編碼不同氨基酸的密碼子。 ^[1]是一種非同義替換（英语：nonsynonymous substitution）。

DNA突變替代蛋白質

錯義突變是指由單個核苷酸點突變引起蛋白質一個氨基酸異化。是DNA序列一種非同義替換（英语：nonsynonymous substitution）。

錯義突變可以使生成的蛋白質失去功能^[2]，導致疾病，如大皰性表皮鬆解症（英语：Epidermolysis bullosa）、鐮狀細胞病、超氧化物歧化酶介導的肌萎縮側索硬化以及癌症.^[3]^[4]

在最常見的鐮狀細胞病變體，血紅蛋白β鏈（英语：beta chain）基因第20個核苷酸從GAG密碼子變為GTG密碼子。因此，第6個氨基酸谷氨酸被纈氨酸取代，標記為E6V突變，並且蛋白質發生充分改變以引起鐮狀細胞病。^[5]

並非所有的錯義突變都會導致明顯蛋白質變化。一種氨基酸可能被化學性質非常相似的氨基酸取代，這種情況，蛋白質可能仍能正常發揮作用；這被稱為保守突變。或者，氨基酸取代可以發生在不顯著影響蛋白質二級結構或功能的蛋白質區域，這或也可被稱為保守突變。

示例

    DNA: 5' - AAC AGC CTG CGT ACG GCT CTC - 3'
         3' - TTG TCG GAC GCA TGC CGA GAG - 5'
   mRNA: 5' - AAC AGC CUG CGU ACG GCU CUC - 3'

蛋白質：Asn Ser Leu Arg Thr Ala Leu

LMNAc.1580G>T錯義突變引入LMNA基因–DNA序列CGT位置1580nt導致鳥嘌呤被胸腺嘧啶取代，產生DNA序列中的CTT。這導致在蛋白質第527位的精氨酸被亮氨酸取代。^[6]這會導致鹽橋（英语：Salt bridge (protein)）破壞和結構不穩定。在表型水平表現為重疊的下頜骨發育不良（英语：mandibuloacral dysplasia）和早衰綜合症（英语：progeria syndrome）。

得到的轉錄物和蛋白質產物是：

    DNA: 5' - AAC AGC CTG CTT ACG GCT CTC - 3'
         3' - TTG TCG GAC GAA TGC CGA GAG - 5'
   mRNA: 5' - AAC AGC CUG CUU ACG GCU CUC - 3'

蛋白質：Asn Ser Leu Leu Thr Ala Leu

實驗分析

癌症相關的錯義突變可導致所得蛋白質的劇烈不穩定。^[7]

2012年提出了一種篩選此類變化的方法，即快速平行蛋白水解（英语：fast parallel proteolysis (FASTpp)）。^[8]

另見

Ka/Ks
Missense mRNA（英语：Missense mRNA）

參考

^ Definition of Missense mutation. MedTerms medical dictionary. MedicineNet. 2012-03-19 [2022-12-28]. （原始内容存档于2013-12-02）.
^ Minde, David P; Anvarian, Zeinab; Rüdiger, Stefan GD; Maurice, Madelon M. Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer?. Molecular Cancer. 1 January 2011, 10 (1): 101. PMC 3170638 . PMID 21859464. doi:10.1186/1476-4598-10-101.
^ Boillée, S; Vande Velde, C; Cleveland, D. W. ALS: A disease of motor neurons and their nonneuronal neighbors. Neuron. 2006, 52 (1): 39–59. PMID 17015226. doi:10.1016/j.neuron.2006.09.018 .
^ Henderson, Mark. A Monumental Breakthrough?. The News-Star. May 1, 2020: A1, A7 [21 November 2022]. （原始内容存档于2022-11-21）（英语）.
^ 141900 Hemoglobin—Beta Locus; HBB: .0243 Hemoglobin S. Sickle Cell Anemia, included. Malaria, Resistance to, included. HBB, GLU6VAL — 141900.0243. Online 'Mendelian Inheritance in Man' (OMIM). [2022-12-28]. （原始内容存档于2023-09-13）.
^ Al-Haggar M, Madej-Pilarczyk A, Kozlowski L, Bujnicki JM, Yahia S, Abdel-Hadi D, Shams A, Ahmad N, Hamed S, Puzianowska-Kuznicka M. A novel homozygous p.Arg527Leu LMNA mutation in two unrelated Egyptian families causes overlapping mandibuloacral dysplasia and progeria syndrome.. Eur J Hum Genet. 2012, 20 (11): 1134–40. PMC 3476705 . PMID 22549407. doi:10.1038/ejhg.2012.77.
^ Bullock, AN; Henckel, J; DeDecker, BS; Johnson, CM; Nikolova, PV; Proctor, MR; Lane, DP; Fersht, AR. Thermodynamic stability of wild-type and mutant p53 core domain. Proc. Natl. Acad. Sci. U.S.A. 23 December 1997, 94 (26): 14338–42. Bibcode:1997PNAS...9414338B. PMC 24967 . PMID 9405613. doi:10.1073/pnas.94.26.14338 .
^ Minde, DP; Maurice, MM; Rüdiger, SG. Determining biophysical protein stability in lysates by a fast proteolysis assay, FASTpp. PLOS ONE. 2012, 7 (10): e46147. Bibcode:2012PLoSO...746147M. PMC 3463568 . PMID 23056252. doi:10.1371/journal.pone.0046147 .

外部鏈接

[1] Definition of Missense mutation. MedTerms medical dictionary. MedicineNet. 2012-03-19 [2022-12-28]. （原始内容存档于2013-12-02）.

[2] Minde, David P; Anvarian, Zeinab; Rüdiger, Stefan GD; Maurice, Madelon M. Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer?. Molecular Cancer. 1 January 2011, 10 (1): 101. PMC 3170638 . PMID 21859464. doi:10.1186/1476-4598-10-101.

[3] Boillée, S; Vande Velde, C; Cleveland, D. W. ALS: A disease of motor neurons and their nonneuronal neighbors. Neuron. 2006, 52 (1): 39–59. PMID 17015226. doi:10.1016/j.neuron.2006.09.018 .

[4] Henderson, Mark. A Monumental Breakthrough?. The News-Star. May 1, 2020: A1, A7 [21 November 2022]. （原始内容存档于2022-11-21）（英语）.

[5] 141900 Hemoglobin—Beta Locus; HBB: .0243 Hemoglobin S. Sickle Cell Anemia, included. Malaria, Resistance to, included. HBB, GLU6VAL — 141900.0243. Online 'Mendelian Inheritance in Man' (OMIM). [2022-12-28]. （原始内容存档于2023-09-13）.

[6] Al-Haggar M, Madej-Pilarczyk A, Kozlowski L, Bujnicki JM, Yahia S, Abdel-Hadi D, Shams A, Ahmad N, Hamed S, Puzianowska-Kuznicka M. A novel homozygous p.Arg527Leu LMNA mutation in two unrelated Egyptian families causes overlapping mandibuloacral dysplasia and progeria syndrome.. Eur J Hum Genet. 2012, 20 (11): 1134–40. PMC 3476705 . PMID 22549407. doi:10.1038/ejhg.2012.77.

[7] Bullock, AN; Henckel, J; DeDecker, BS; Johnson, CM; Nikolova, PV; Proctor, MR; Lane, DP; Fersht, AR. Thermodynamic stability of wild-type and mutant p53 core domain. Proc. Natl. Acad. Sci. U.S.A. 23 December 1997, 94 (26): 14338–42. Bibcode:1997PNAS...9414338B. PMC 24967 . PMID 9405613. doi:10.1073/pnas.94.26.14338 .

[8] Minde, DP; Maurice, MM; Rüdiger, SG. Determining biophysical protein stability in lysates by a fast proteolysis assay, FASTpp. PLOS ONE. 2012, 7 (10): e46147. Bibcode:2012PLoSO...746147M. PMC 3463568 . PMID 23056252. doi:10.1371/journal.pone.0046147 .

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