Nonsense mutation

[5] The example above begins with a 5' DNA sequence with 24 nucleotides (8 triplet codons) seen and its complementary strand shown below.

The codons corresponding to the fourth amino acid, Arginine (Arg), are highlighted because they will undergo a nonsense mutation in the following figure of this example.

An example of this type of nonsense mutation is one that occurs directly before the original stop codon for that given protein.

[2][8] Because a nonsense mutation introduces a premature stop codon within a sequence of DNA, it is extremely unlikely that this scenario can actually benefit the organism.

Stopping this protein from performing at full strength causes less toxin to be released and the fitness of the organism to be improved.

[8] Nonsense-mediated mRNA decay Despite an expected tendency for premature termination codons to yield shortened polypeptide products, in fact the formation of truncated proteins does not occur often in vivo.

Many organisms—including humans and lower species, such as yeast—employ a nonsense-mediated mRNA decay pathway, which degrades mRNAs containing nonsense mutations before they are able to be translated into nonfunctional polypeptides.

[10] Nonsense mutations comprise around 20% of single nucleotide substitutions within protein coding sequences that result in human disease.

[13][12] Translation of the remaining nonsense-bearing mRNA may generate abbreviated protein variants with toxic effects.

[14] Twenty-three different single-point nucleotide substitutions are capable of converting a non-stop codon into a stop-codon, with the mutations CGA

TAG being the most common disease-related substitutions characterized in the Human Gene Mutation Database (HGMD).

[17] An LGR4 nonsense mutation in a healthy population has been linked to low bone mass density and symptoms of osteoporosis.

[18] Antisense oligonucleotides to suppress the expression of NMD and translation termination proteins are being explored in animal models of nonsense mutation-induced disease.

[18][19] Other RNA therapeutics under investigation include synthetic suppressor tRNAs that enable ribosomes to insert an amino acid, instead of initiating chain termination, upon encountering premature stop codons.

[18] An oxadiazole, ataluren (previously PTC124), facilitates the selective read-through of aberrant stop codons, rendering it a potential therapeutic against nonsense mutation-induced disease.

[21] Ataluren, sold under the tradename Translarna, is currently an approved treatment for Duchenne muscular dystrophy in the European Economic area and Brazil.

[22][23] However, phase III trials of Ataluren as a cystic fibrosis therapeutic have failed to meet their primary endpoints.

Pictured on the left is a diagram of normal translation occurring without mutation. Blue circles are the peptides already translated while the grey circles are peptides going to be translated next. In the center is a diagram a nonsense mutation where the UUG codon is translated to the stop codon UAG. The stop codon recruits a release factor, terminating translation. On the right is a diagram of the tRNA suppression mechanism where the codon and the tRNA are both mutated, resulting in tRNA suppression. The mutated Tyr tRNA has the anticodon AUC which recognizes the UAG stop codon, continuing protein translation. [ 9 ]
Selection of notable mutations, ordered in a standard table of the genetic code of amino acids . [ 11 ] nonsense mutations are marked by red arrows.