Nonsense mutation

Nonsense mutation
n., plural: nonsense mutations
[ˈnɑnsɛns mjuˈteɪʃən]
Definition: a mutation that leads to a premature stop codon

A nonsense mutation is the type of point mutation that renders the translation process useless by coding for a stop/nonsense codon. Since this would lead to the generation of an early truncated or non-functional protein, an mRNA-mediated decay process degrades the useless mRNA even before it’s translated.

Genome is a dynamic entity. Although commonly perceived as static because of the widely known and relatively stable nature of DNA, the genome is subject to an array of heritable genetic changes. Heritable genetic changes in the nucleotide sequence/s of the genome are called genetic mutations.

By the end of this article, you will not only be able to define nonsense mutation but also know where to place this type of mutation, the mechanism by which it develops, and answer the common questions like how it’s different from the other types of point mutations in the coding region of the genome, which type of mutation always produces a stop codon, and how do mutations affect an organism…

Nonsense Mutation Definition

What is a nonsense mutation? In biology, a nonsense mutation is a type of point mutation arising due to replication error and resulting in the generation of a nonsense codon/stop codon. This stop codon does not code for amino acid and leads to a protein product that is early truncated (shortened protein) and the resulting protein is thereby non-functional. Since the nonsense point mutation codes for a premature stop codon, it can also be called stop mutation.

Mutations help in giving rise to alternative forms of the same gene. This process of occurrence of genetic mutation is called mutagenesis while the organism in which a mutation manifests in the form of a phenotypic change is called mutant. Now, after this brief description of the mutation process, let’s learn in detail about nonsense mutations. We will cover the different types of mutations of which one type is a nonsense mutation.

Watch this vid about nonsense mutations:

Types of Mutations and Placement of Nonsense Mutation

Mutations can be classified into two types — spontaneous and induced mutations. Spontaneous mutations are the ultimate source of natural genetic variations in populations. They develop spontaneously. They develop even in the absence of a mutagen (mutagenic agent). On the other hand, induced mutations don’t develop spontaneously and are induced by physical, biological, or chemical mutagens.

Mechanisms Causing Spontaneous Mutations

There are three mechanisms by which spontaneous mutations can arise. They are:

1. Due to replication error – two subtypes: Point mutations and Frameshift mutations
2. Due to spontaneous lesion – two subtypes: Deamination, Depurination/Depyrimidination, Oxidative damage
3. Spontaneous mutations

Point Mutations Overview

Point mutations (literally stand for mutation at a definite point) are the mutations where only one nucleotide change is involved. Point mutations can occur in different parts of the genome.

• If point mutation occurs in the non-coding region of the genome, it doesn’t result in an altered amino acid sequence during the translation process.
• If point mutation occurs in the coding region of the genome, it holds the potential to alter the gene sequence/s and thereby altering the amino acid it codes for. This eventually alters the protein sequence, structure, and function. This at last results in an apparent change in gene expression.

Outcomes of a Nonsense Mutation

A nonsense mutation in a gene can result in different types of outcomes ranging from deleterious to neutral to beneficial. Let’s briefly look at the different nonsense mutations.

• Deleterious

  • Nonsense mutations that lead to the truncation of a protein that performs a vital function in the body will turn out to be deleterious mutations. When such nonsense mutation occurs, it leads to an overall decline in the reproductive fitness and success of the organisms, hence sometimes called harmful mutations.
  • Nonsense mutations of this nature are the most common ones.
  • Example: Mutation in the ion channel protein (CFTR protein) or alpha-globin and beta-globin producing genes (hemoglobin protein).

• Neutral

  • Nonsense mutations that go undetected due to no apparent change in the protein functioning and effects are recognized as neutral in nature. When such nonsense mutations occur, the organism is neither positively affected nor negatively affected.
  • Nonsense mutations of this nature are less common than deleterious ones.
  • Example: Mutation at the site exactly before the very last amino acid of a protein.

• Beneficial

  • Nonsense mutations that lead to an overall increase in the reproductive fitness and success of the organisms are recognized as beneficial in nature.
  • Nonsense mutations of this nature are the least common ones.
  • Example: Mutation at a site that affects a channel protein in selectively eliminating the transportation of toxins from external to cell’s internal environment.

So, now when asked “what is the effect of a nonsense mutation”, we can explain each of the above situations.

Nonsense Mutation Example

Let’s try to put forth a hypothetical example to make you understand the ‘nonsense mutation concept’.

• Example to understand the difference between “Nonsense mutation” and the other 3 types

Consider we have a hypothetical codon ABC coding for arginine (a basic amino acid).

1. Change from ABC to ABB: ABB also coding for arginine. This is a silent mutation. This change at the genotypic level didn’t change the amino acid coded or any change in the protein that the amino acid further codes for.
2. Change from ABC to AAA: AAA coding for lysine. Lysine is another basic amino acid. This is a neutral mutation. This change at the genotypic level changed the amino acid coded (from arginine to lysine). But, the nature of amino acids is the same (both are basic). This rarely changes the protein coded for or the protein function.
3. Change from ABC to AAC: AAC coding for aspartate. Aspartate is an acidic amino acid. This is a missense mutation. This change at the genotypic level changed the amino acid coded (arginine to aspartate) and also changed the nature of amino acids (basic to acidic). This will change the protein coded for and the protein function.
4. Change from ABC to ACC: ACC coding for stop codon/nonsense codon. This is called a nonsense mutation. This change at genotypic level codes for “NO AMINO ACID”. No amino acid means that the protein product would either be incomplete or non-functional or not formed at all. This results due to the early truncation and leads to the termination of the translation process.

• Synonymous versus Non-synonymous mutation

If asked to place nonsense mutation in one of these categories, where will you place it; synonymous or non-synonymous?

• • Synonymous mutation: No change in amino acid. (Example: silent mutation)
  • Nonsynonymous mutation: Change in amino acid/amino acid mutations/ different amino acid (Example: neutral mutation, missense mutation, nonsense mutation)

Nonsense-mediated mRNA decay

Nonsense-mediated mRNA decay is a process by which an organism’s body ensures to degrade all the premature/truncated/shortened proteins. More common than premature protein degradation is the decay of the mRNA itself that is containing these nonsense mutations.

This nonsense-mediated mRNA decay occurs in many organisms like human beings, yeasts, etc. This mechanism ensures that the nonsense variant of mRNA which can potentially lead to severe genetic diseases or genetic disorders is completely degraded before it is translated to useless non-functional proteins. It can be called a smart energy saver and surveillance step.

Pathology Associated with Nonsense Mutations

Nonsense mutations have the potential to cause a range of genetic diseases or disorders since they prevent the successful completion of the translation process of some functionally vital proteins. An important point to note here is that these diseases can be caused by some other type of mutations too in the same gene.

Some popularly known pathologies associated with nonsense mutations are:

1. 1. Cystic fibrosis:

      It is caused due to a nonsense mutation in the CFTR protein (an ion channel membrane protein) at position 542. The mutation is called G542X mutation as the codon coding for glycine (G) is replaced by a stop codon (X).

      

   2. Beta thalassemia:

      It is caused due to a nonsense mutation in the beta-globin chain of the hemoglobin protein. Since hemoglobin is the main oxygen-carrying protein in the RBCs, patients with beta-thalassemia have compromised oxygen levels reaching their vitals.

      

   3. Hurler syndrome:

      It is caused due to a nonsense mutation in the IDUA gene that codes for the alpha-L-iduronidase enzyme. This enzyme is responsible for the breakdown of GAGs (a complex sugar). A deficit or absence of this enzyme can be detrimental to the limit of death in children.

      

• Duchenne muscular dystrophy:

  It is caused by a nonsense mutation in the DMD gene coding for dystrophin protein. This is more common in males than females. Ataluren is currently being used to treat Duchenne muscular dystrophy.

  

Answer the quiz below to check what you have learned so far about nonsense mutations.

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References

• Jennings, M. T., Riekert, K. A., & Boyle, M. P. (2014). Update on key emerging challenges in cystic fibrosis. Medical principles and practice : international journal of the Kuwait University, Health Science Centre, 23(5), 393–402. https://doi.org/10.1159/000357646
• Thein SL. The molecular basis of β-thalassemia. Cold Spring Harb Perspect Med. 2013 May 1;3(5):a011700. doi: 10.1101/cshperspect.a011700. PMID: 23637309; PMCID: PMC3633182.
• Kazazian H. H., Jr (2021). A Long, Fulfilling Career in Human Genetics. Annual review of genomics and human genetics, 22, 27–53. https://doi.org/10.1146/annurev-genom-111620-095614
• Haas, M., Vlcek, V., Balabanov, P., Salmonson, T., Bakchine, S., Markey, G., Weise, M., Schlosser-Weber, G., Brohmann, H., Yerro, C. P., Mendizabal, M. R., Stoyanova-Beninska, V., & Hillege, H. L. (2015). European Medicines Agency review of ataluren for the treatment of ambulant patients aged 5 years and older with Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene. Neuromuscular disorders : NMD, 25(1), 5–13. https://doi.org/10.1016/j.nmd.2014.11.011
• Gatfield D, Unterholzner L, Ciccarelli FD, Bork P, Izaurralde E (1 August 2003). “Nonsense-mediated mRNA decay in Drosophila: at the intersection of the yeast and mammalian pathways”. The EMBO Journal. 22 (15): 3960–70. doi:10.1093/emboj/cdg371. PMC 169044. PMID 12881430

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