错义突变

在遗传学，错义突变是一种点突变，其中单个核苷酸变化导致编码不同氨基酸的密码子。 ^[1]是一种非同义替换（英语：nonsynonymous substitution）。

DNA突变替代蛋白质

此图像显示错义突变的示例。DNA序列的一个核苷酸（腺嘌呤）被另一个核苷酸（胞嘧啶）取代。这导致错误的氨基酸（脯氨酸）被整合到蛋白质序列中。

错义突变是指由单个核苷酸点突变引起蛋白质一个氨基酸异化。是DNA序列一种非同义替换（英语：nonsynonymous substitution）。

错义突变可以使生成的蛋白质失去功能^[2]，导致疾病，如大疱性表皮松解症（英语：Epidermolysis bullosa）、镰状细胞病、超氧化物歧化酶介导的肌萎缩侧索硬化以及癌症.^[3]^[4]

在最常见的镰状细胞病变体，血红蛋白β链（英语：beta chain）基因第20个核苷酸从GAG密码子变为GTG密码子。因此，第6个氨基酸谷氨酸被缬氨酸取代，标记为E6V突变，并且蛋白质发生充分改变以引起镰状细胞病。^[5]

并非所有的错义突变都会导致明显蛋白质变化。一种氨基酸可能被化学性质非常相似的氨基酸取代，这种情况，蛋白质可能仍能正常发挥作用；这被称为保守突变。或者，氨基酸取代可以发生在不显著影响蛋白质二级结构或功能的蛋白质区域，这或也可被称为保守突变。

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'

蛋白质：Asn Ser Leu Arg Thr Ala Leu

LMNAc.1580G>T错义突变引入LMNA基因–DNA序列CGT位置1580nt导致鸟嘌呤被胸腺嘧啶取代，产生DNA序列中的CTT。这导致在蛋白质第527位的精氨酸被亮氨酸取代。^[6]这会导致盐桥（英语：Salt bridge (protein)）破坏和结构不稳定。在表型水平表现为重叠的下颌骨发育不良（英语：mandibuloacral dysplasia）和早衰综合症（英语：progeria syndrome）。

得到的转录物和蛋白质产物是：

    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'

蛋白质：Asn Ser Leu Leu Thr Ala Leu

实验分析

癌症相关的错义突变可导致所得蛋白质的剧烈不稳定。^[7]

2012年提出了一种筛选此类变化的方法，即快速平行蛋白水解（英语：fast parallel proteolysis (FASTpp)）。^[8]

另见

Ka/Ks
Missense mRNA（英语：Missense mRNA）

参考

^ 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  .

外部链接

[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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