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In genetics, a missense mutation (a type of nonsynonymous substitution) is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. Another type of nonsynonymous substitution is a nonsense mutation in which a codon is changed to a premature stop codon that results in truncation of the resulting protein. Missense mutations can render the resulting protein nonfunctional, and such mutations are responsible for diseases such as Epidermolysis bullosa, sickle-cell disease, and SOD1 mediated ALS (Boillée 2006, p. 39).
The most common variant of sickle-cell disease, the 20th nucleotide of the gene for the beta chain of hemoglobin is altered from the codon GAG to GTG. Thus, the 6th amino acid glutamic acid is substituted for valine — notated as an "E6V" mutation — and the protein is sufficiently altered to cause the sickle-cell disease.
Not all missense mutations lead to appreciable protein changes. An amino acid may be replaced by an amino acid of very similar chemical properties, in which case, the protein may still function normally; this is termed a neutral, "quiet", "silent" or conservative mutation. Alternatively, the amino acid substitution could occur in a region of the protein which does not significantly affect the protein secondary structure or function. When an amino acid may be encoded by more than one codon (so-called "degenerate coding") a mutation in a codon may not produce any change in translation; this would be a silent mutation (a type of synonymous substitution, which is not always silent) and not a missense mutation.
DNA: 5' - ATG ACT CAC CAC GCG CGA AGC TGA - 3' 3' - TAC TGA GTG GTG CGC GCT TCG ACT - 5' mRNA: 5' - AUG ACU CAC CAC GCG CGA AGC UGA - 3' Protein: Met Thr His His Ala Arg Ser Stop
Suppose that a missense mutation was introduced at the fourth triplet in the DNA sequence (CAC) causing the adenine to be replaced with cytosine, yielding CCC in the DNA sequence. The resulting transcript and protein product would be:
DNA: 5' - ATG ACT CAC CCC GCG CGA AGC TGA - 3' 3' - TAC TGA GTG GGG CGC GCT TCG ACT - 5' mRNA: 5' - AUG ACU CAC CCC GCG CGA AGC UGA - 3' Protein: Met Thr His Pro Ala Arg Ser Stop
Cancer associated missense mutations can lead to drastic destabilisation of the resulting protein. A novel method to screen for such changes was proposed recently, namely Fast parallel proteolysis (FASTpp).
- MedTerms™ Medical Dictionary http://www.medterms.com/script/main/art.asp?articlekey=4396
- Minde, David P; Anvarian, Zeinab; Rüdiger, Stefan GD; Maurice, Madelon M (1 January 2011). "Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer?". Molecular Cancer 10 (1): 101. doi:10.1186/1476-4598-10-101. PMC 3170638. PMID 21859464.
- OMIM 141900.0243
- Bullock, AN; Henckel, J; DeDecker, BS; Johnson, CM; Nikolova, PV; Proctor, MR; Lane, DP; Fersht, AR (Dec 23, 1997). "Thermodynamic stability of wild-type and mutant p53 core domain.". Proceedings of the National Academy of Sciences of the United States of America 94 (26): 14338–42. doi:10.1073/pnas.94.26.14338. PMC 24967. PMID 9405613.
- Minde, DP; Maurice, MM; Rüdiger, SG (2012). "Determining biophysical protein stability in lysates by a fast proteolysis assay, FASTpp.". PLoS ONE 7 (10): e46147. doi:10.1371/journal.pone.0046147. PMC 3463568. PMID 23056252.
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- Boillée, Séverine; Vande Velde, C; Cleveland, DW (2006), "ALS: A Disease of Motor Neurons and Their Nonneuronal Neighbors", Neuron 52 (1): 39–59, doi:10.1016/j.neuron.2006.09.018, PMID 17015226.
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