In genetics , a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon , or a nonsense codon in transcribed mRNA , and in a truncated , incomplete, and generally inert protein product. [1] The functional effect of a nonsense mutation depends on the location of the stop codon within the coding DNA. 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. [2]
A nonsense mutation differs from a missense mutation , which is a point mutation where a single nucleotide is changed due to the 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. Some genetic disorders , such as thalassemia and cystic fibrosis [3] result from nonsense mutations.
Simple example
DNA : 5′ – ATG Act CAC CGA GCG CGA AGC TGA – 3′ 3′ – TAC TGA GTG GCT CGC GCT TCG Act – 5′ mRNA : 5′ – Aug ACU CAC CGA GCG CGA AGC UGA -3′
Protein: Met Thr His Arg Ala Arg Ser Stop
Suppose a nonsense mutation was introduced in the fourth triplet in the DNA sequence (CGA), which caused cytosine to be replaced with thymine , TGA in the DNA sequence and ACT in the complementary strand. Since ACT is written as UGA and then translated, the resulting transcript and protein product would be:
DNA : 5′ – ATG Act CAC TGA GCG CGA AGC TGA – 3′ 3′ – TAC TGA GTG Act CGC GCT TCG Act – 5′ mRNA : 5′ – Aug ACU CAC UGA GCG CGU AGC UGA -3′
Protein: Met Thr His Stop
The remaining codons of the mRNA are not translated into proteins because the stop codon is reached prematurely during translation. This can generate a truncated (i.e., abridged) protein product, which often lacks the functionality of a normal, non-mutant protein.
Nonsense-mediated mRNA decay
Despite the expected propensity of premature termination codons to yield short polypeptide products, the formation of truly truncated proteins does not occur frequently 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 being able to translate them into non-functional polypeptides.
Pathology associated with nonsense mutations
Nonsense mutations can cause a genetic disease by preventing the complete translation of a specific protein. However, the same disease can be caused by other types of damage to the same gene. Examples of diseases in which nonsense mutations cause include:
- Cystic fibrosis (caused by the G542X mutation in the cystic fibrosis transmembrane conductance regulator (CFTR))
- Beta Thalassemia (β-Globin)
- Hurler syndrome
- Dravet syndrome
Ataluren (previously PTC124) is a pharmaceutical drug that can be used to treat genetic diseases caused by nonsense mutations. It is currently being used to treat Duchenne muscular dystrophy. [5] Clinical trials for the treatment of cystic fibrosis are ongoing.
