Nonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a nonsense codon, or a premature stop codon in the transcribed mRNA, and leads to a truncated, incomplete, and possibly nonfunctional protein product.[1] Nonsense mutations are not always harmful;[2] the functional effect of a nonsense mutation depends on many aspects, such as the location of the stop codon within the coding DNA.[2] For example, the effect of a nonsense mutation depends on the proximity of the nonsense mutation to the original stop codon, and the degree to which functional subdomains of the protein are affected.[3] As nonsense mutations leads to premature termination of polypeptide chains; they are also called chain termination mutations.[4]
Missense mutations differ from nonsense mutations since they are point mutations that exhibit a single nucleotide change to cause substitution of a different amino acid. A nonsense mutation also differs from a nonstop mutation, which is a point mutation that removes a stop codon. About 10% of patients facing genetic diseases have involvement with nonsense mutations.[5] Some of the diseases that these mutations can cause are Duchenne muscular dystrophy (DMD), cystic fibrosis (CF),[6] spinal muscular atrophy (SMA), cancers, metabolic diseases, and neurologic disorders.[5][7] The rate of nonsense mutations is variable from gene-to-gene and tissue-to-tissue, but gene silencing occurs in every patient with a nonsense mutation.[5]
Possible outcomes[edit]
Deleterious[edit]
Deleterious outcomes represent the majority of nonsense mutations and are the most common outcome that is observed naturally. Deleterious nonsense mutations decreases the overall fitness and reproductive success of the organism.[8] For example, a nonsense mutation occurring in a gene encoding a protein can cause structural or functional defects in the protein that disrupt cellular biology. Depending on the significance of the functions of this protein, this disruption now could be detrimental to the fitness and survival of that organism.[8]
Neutral[edit]
When a nonsense mutation is neutral, it does not provide benefits or harm. These occur when the effects of the mutation are unnoticed. In other words, this means that the mutation does not positively or negatively affect the organism. As this effect is unnoticed, there is a lack of papers describing such mutations. An example of this type of nonsense mutation is one that occurs directly before the original stop codon for that given protein.[8] Because this mutation occurred in such close proximity to the end of the protein chain, the impact of this change might not be as significant. This would suggest that this amino acid that was mutated did not have a large impact on the overall structure or function of the protein or the organism as a whole. This scenario is rare, but possible.[8]
Beneficial[edit]
Beneficial nonsense mutations are considered as the rarest of possible nonsense mutation outcomes. Beneficial nonsense mutations increase the overall fitness and reproductive success of an organism, opposite of the effects of a deleterious mutation.[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.[1] An example of this would occur with a nonsense mutation that impacts a dysfunctional protein that releases toxins. The stop codon that this mutation brings would stop this dysfunctional protein from properly carrying out its function. Stopping this protein from performing at full strength causes less toxin to be released and the fitness of the organism to be improved. These types of situations with nonsense mutations occur a lot less frequently than the deleterious outcomes.[8]
Therapeutics targeting nonsense mutation diseases[edit]
Therapeutics for diseases caused by nonsense mutations attempt to recapitulate wild-type function by decreasing the efficacy of NMD, facilitating readthrough of the premature stop codon during translation, or editing the genomic nonsense mutation.[17]
Antisense oligonucleotides to suppress the expression of NMD and translation termination proteins are being explored in animal models of nonsense mutation-induced disease.[17][18] 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.[17]
CRISPR-Cas9 based single nucleotide substitutions have been used to generate amino acid codons from stop codons, achieving an editing success rate of 10% in cell cultures.[19]
Read-through has been achieved using small molecule drugs such as aminoglycosides and negamycin.[17] An oxadiazole, ataluren (previously PTC124), facilitates the selective read-through of aberrant stop codons, rendering it a potential therapeutic against nonsense mutation-induced disease.[20] Ataluren, sold under the tradename Translarna, is currently an approved treatment for Duchenne muscular dystrophy in the European Economic area and Brazil.[21][22] However, phase III trials of Ataluren as a cystic fibrosis therapeutic have failed to meet their primary endpoints.[23][24]