Missense Mutations

Missense Mutations

A missense mutation is a change in the nucleic acid base sequence (e.g., the polynucleotide sequence found in DNA) that results in a change in the order of amino acids in the protein chain resulting from the translation of that sequence.

As with all mutations, a missense mutation is a change in a gene or chromosome. There are many types of mutations, including those resulting in a substitution of bases in the DNA sequence (i.e., one nucleotide is exchanged for another in the polynucleotide sequence. The effects of these mutations depend on the type, extent, and placement of the mutation in the DNA sequence. The effects of mutations range from silent mutations that do not result in a change in the translated protein sequence to mutations that are lethal and prevent embryonic development.

Changes in DNA sequencing are natural. Changes that occur during replication are usually repaired by specialized DNA repair mechanisms. When these mechanisms fail to correct a change, (revert the sequence of bases back to their normal state) a mutation results. As a result of a missense mutation, instead of the insertion of the proper amino acid into the chain of amino acids bonded together to form a protein, another amino acid is inserted. Unless there is another mutation in a gene that codes for a transfer RNA (tRNA) that allows the suppression of a missense mutation, the structure and function of the protein can be dramatically altered by the improper substitution of an amino acid.

A well-known example of a missense mutation occurs with the sickle cell gene. A substitution of thymine for adenine at the nucleotide 17 of the gene that contains the instructions to construct the beta chain of the hemoglobin molecule results in a substitution of the amino acid valine for the amino acid glutamic acid in the beta chain. This subtle alteration of genetic sequence results in profound changes in the shape and physiological responses of the hemoglobin molecule that, in turn, can lead to sickle cell disease. At the molecular level, the substitution of thymine for adenine results in a change in the three base (triplet) sequence that determines the codon sequence. Instead of a glutamine-adenine-glutamine (GAG) triplet that instructs the insertion of glutamic acid into the growing protein molecule during translation, a codon is constructed from a glutamine-thymine-glutamine (GTG) triplet that codes for valine.

For example, if the base sequence of the coding stand of DNA is GAG, because of restricted base paring (e.g., A-T and C-G) the anticoding DNA strand used as a transcription template contains a CTC sequence. Because uracil (U) replaces thymine in mRNA, the DNA coding strand sequence (the strand that has the same sequence as does the mRNA transcript) results in a mRNA codon sequence of GAG. This codon sequence is ultimately translated to insert glutamic acid into the translated protein's sequence of amino acids. A missense mutation resulting in the substitution of thymine (T) for adenine (A) in the coding strand sequence results in DNA sequence of GTG that results in a GUG mRNA codon. As a result of the missense mutation, and the changes in the codons transcribed. Instead of the insertion of the amino acid glutamic acid into the lengthening amino acid chain during the translation process, the amino acid valine is inserted in its place.

Missense mutation suppressors are similar to nonsense mutation suppressor in that are mutant genes that result in the production of transfer ribonucleic acids (tRNA) that have anticodons altered so that they have the ability to correct the errant instructions produced by missense mutations. In addition to DNA repair mechanisms, extragenic suppressor mutations termed missense mutation suppressors can also allow the proper synthesis of proteins despite the presence of a missense mutation.