# Missense Mutation

In genetics , a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid . [1] It is a type of non-synonymous substitution .

## Replacement of protein by DNA mutation

Missense mutation refers to a change in an amino acid in a protein, resulting from a point mutation in a single nucleotide . Missense mutation is a type of non-synonymous substitution in the DNA sequence . Two other types of non-synonymous substitutions are nonsense mutation – in which a codon is truncated into a premature stop codon, resulting in truncated protein – and nonstop mutation – in which deletion of a stop codon results in a long, non-stop codon. Contains functional proteins. ,

Missense mutations can render the resulting protein non-functional, [2] and such mutations are responsible for human diseases such as epidermolysis bullosa , sickle-cell disease and SOD1 – mediated ALS .

In the most common form of sickle cell disease, the 20th nucleotide of the gene for the beta chain of hemoglobin is changed from the codon GAG to GTG . Thus, the sixth amino acid glutamic acid is replaced by valine – known as an “E6V” mutation – and the protein is altered enough to cause sickle cell disease. [4]

Not all missense mutations lead to appreciable protein changes. An amino acid can be replaced by an amino acid of very similar chemical properties, in which case, the protein can still function normally; This is called a neutral, “quiet”, “silent” or stereotypical mutation. Alternatively, amino acid substitution may occur in a region of the protein that does not significantly affect the secondary structure or function of the protein. When an amino acid can be encoded by more than one codon (so-called “degenerate coding”), a mutation in the codon may not cause any change in translation; This would be a synonymous substitution and not a missense mutation.

#### Example

DNA: 5′ – AAC AGC CTG CGT ACG GCT CTC – 3′ 3′ – TTG TCG GAC GCA TGC CGA GAG – 5′ m

RNA: 5′ – AAC AGC CUG CGU ACG GCU CUC – 3′ Protein: Asn Ser Leu Arg Thr ala lue

The LMNA missense mutation (c.1580G>T) was introduced into the DNA sequence (CGT) at the LMNA gene-position 1580 (nt), replacing guanine with thymine , which generates a CTT in the DNA sequence. This results in the replacement of arginine by leucine at position 527 at the protein level . [5] This leads to the destruction of the salt bridge and the structure is unstable. At the phenotype level this manifests with overlapping mandibuloacral dysplasia and progeria syndrome.

The resulting transcript and protein product is:

DNA: 5' - AAC AGC CTG CTT ACG GCT CTC - 3' 3' - TTG TCG GAC GAA TGC CGA GAG - 5' m
RNA: 5' - AAC AGC CUG CuU ACG GCU CUC - 3' Protein: Asn Ser Liu Liu Thr ala liu

## Experimental analysis

Cancer-associated missense mutations can lead to massive destabilization of the resulting protein. [6] In 2012 a method to investigate such changes was proposed, named Fast Parallel Proteolysis (FASTpp).