A nonsense mutation refers to a type of genetic mutation in which a premature stop codon is introduced into a DNA sequence, disrupting the normal translation process of a protein-coding gene.
This type of mutation is categorized as a loss-of-function change, as it impairs or completely prevents the production of a specific protein.
Similar to other mutations, nonsense mutations can produce a range of effects on protein synthesis and function, depending on the context of the mutation.
Since the resulting truncated proteins are typically unstable and rapidly degraded by proteasomes, a nonsense mutation often has a functional effect equivalent to a complete deletion of the affected gene.
The specific impact of a nonsense mutation is influenced by the position of the premature stop codon and how far it is from the upstream coding sequence.
In rare situations, a nonsense mutation may act like a silent mutation, especially if the stop codon is introduced immediately before the last amino acid of the protein, leaving the protein’s function unaffected.
There are also instances where a nonsense mutation may be beneficial, as the resulting change in the amino acid sequence can potentially enhance the organism's fitness and reproductive success.
The stop codons generated as a result of these mutations are referred to as nonsense codons because they do not encode any amino acids and instead serve to regulate or terminate the translation process.
Causes of nonsense mutation
Nonsense mutations occur due to the introduction of a nucleotide change in the DNA sequence that results in the creation of a premature stop codon.
This conversion of a normal codon into a stop codon can happen through either the insertion of an extra nucleotide sequence or the deletion of a nucleotide from the existing sequence.
Such mutations can arise spontaneously during DNA replication or can be induced by external agents known as mutagens.
Spontaneous mutations result from errors made during the natural processing of the DNA sequence, particularly during replication.
Induced mutations occur when the DNA is exposed to external physical factors such as radiation or chemical substances that alter the nucleotide structure.
Certain chemical agents, including reactive oxygen species (ROS), are also capable of causing mutations by targeting specific nucleotides within the DNA sequence.
Spontaneous nonsense mutations often take place on single-stranded DNA segments that are temporarily exposed during the process of replication.
In some cases, mutations may be induced during replication as a result of enzymatic digestion by nucleases that break down the DNA strand.
Mechanism of nonsense mutation
The mechanism behind a nonsense mutation varies depending on its underlying cause, but the most frequently observed mechanism is tautomerism.
Nucleotides can exist in two tautomeric forms: the more common keto form and the rarer enol form. The keto form typically forms stable hydrogen bonds with complementary nucleotides.
During mutation, the keto form may convert into the enol form due to ionization or interaction with certain molecules.
This tautomeric shift alters the hydrogen bonding pattern between nucleotides, which can subsequently disrupt the normal amino acid sequence during translation.
In addition to tautomerism, some mutagens can become incorporated into the DNA sequence, causing the insertion of incorrect nucleotides. These insertions alter the codon sequence.
Enzymatic activity, especially during replication, can lead to the digestion or removal of certain nucleotides, which results in the loss of bases and formation of new codons.
Specifically in nonsense mutations, the premature formation of stop codons—UAG, UAA, or UGA—terminates translation before the full protein is synthesized.
These premature stop codons can arise from various single-nucleotide changes, making multiple mutational pathways possible for generating nonsense codons.
Applications of nonsense mutation
Nonsense mutations have therapeutic applications, particularly in preventing the synthesis of harmful or cancerous proteins by introducing premature stop codons to halt their production.
These mutations can sometimes lead to advantageous genetic changes that improve the fitness, adaptability, and survival of organisms within their natural environments.
Research indicates that nonsense mutations are responsible for approximately 5–15% of all mutations that cause human diseases, highlighting their clinical significance.
In laboratory settings, nonsense mutations are deliberately introduced to study the structure, function, and stability of various proteins, aiding in understanding gene expression and protein folding mechanisms.
Examples of nonsense mutation
Beta thalassemias are a group of inherited blood disorders that result from point nonsense mutations in the gene responsible for producing the beta chains of hemoglobin.
The clinical outcomes of such mutations can vary widely, ranging from severe forms of anemia to cases with little or no noticeable symptoms, depending on the exact location of the mutation within the gene.
These point mutations can occur either through the substitution of a single nucleotide base or the deletion of a nucleotide from the gene sequence.
In cases of substitution, the mutation typically occurs near the promoter regions located upstream of the beta-globin genes, affecting gene regulation and expression.
In deletion cases, specific nucleotides near the upstream region of the beta-globin gene are removed, which disrupts the reading frame or coding sequence.
Both types of mutations ultimately result in the formation of a premature stop codon, which halts the translation process and prevents the complete synthesis of the beta-globin protein.
References
Berkowitz, D., et al. (1968). A procedure for identifying nonsense mutations. Journal of Bacteriology, 96(1), 215–220. https://doi.org/10.1128/JB.96.1.215-220.1968
Jopling, C. L. (2014). Stop that nonsense!. eLife, 3, e04300. https://doi.org/10.7554/eLife.04300
Torella, A., et al. (2020). The position of nonsense mutations as a predictor of phenotype severity: A comprehensive analysis of the DMD gene. PLOS ONE, 15(8), e0237803. https://doi.org/10.1371/journal.pone.0237803
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