Nonsense Mutations Causing Inherited Diseases: Therapeutic Approaches


Nonsense mutations are single nucleotide variations within the coding sequence of a gene that result in a premature termination codon (PTC). The occurrence of such PTCs most often leads to a complete loss of protein function and a reduction in messenger ribonucleic acid (mRNA) levels due to the nonsense‐mediated mRNA decay (NMD), a cellular surveillance mechanism that triggers selective degradation of mutant transcripts. Therapeutic approaches to circumvent the consequences of nonsense mutations may act at different levels: (1) the genomic deoxyribonucleic acid (DNA) by replacing the defective gene; (2) the mRNA by inducing the excision of the mutation‐bearing exon during splicing, or by inhibiting the NMD‐associated degradation and (iii) the protein by suppressing the premature termination of translation using transfer ribonucleic acid (tRNA) suppressors or drugs inducing readthrough. Indeed, a combination of these approaches may be necessary, and it is most likely that they will lead to a mutation‐specific, personalised medicine.

Key Concepts

  • Nonsense mutations may lead to loss or gain of function pathological mechanisms.
  • Premature termination codons (PTCs) resulting from nonsense mutations trigger transcript degradation through the nonsense‐mediated mRNA decay (NMD) mechanism.
  • Mutant mRNA escaping NMD lead to the synthesis of truncated proteins potentially deleterious.
  • Skipping of nonsense mutation‐bearing exons can be induced by antisense oligonucleotides and leads to internally deleted proteins that retain some functionality.
  • tRNA suppressors enable the reintroduction of a ‘sense’ amino acid and the translation of the full‐length protein by competing with the termination factor eRF1.
  • Drug‐induced readthrough of PTCs may allow synthesis of full‐length functional proteins.
  • Synergetic action between NMD inhibitors and readthrough inducers may potentialise reexpression of full‐length proteins with restored functionality.
  • Therapeutic approaches will most likely be mutation and disease specific.

Keywords: nonsense mutations; premature termination codons; inherited disorders; therapeutic approaches; exon skipping; antisense oligonucleotides; nonsense‐mediated decay; tRNA suppressors; readthrough; aminoglycosides

Figure 1. Therapeutic approaches may be applied at different levels: (i) on the genomic DNA, by replacing the gene harbouring a nonsense mutation (PTC); (ii) on the splicing of the pre‐mRNA by inducing the skipping of the mutation‐bearing mRNA; (iii) on the mRNA by preventing its degradation by the nonsense‐mediated mRNA decay (NMD) and (iv) on the translation of the mRNA by forcing the insertion of an amino acid in the nascent polypeptide. The first two approaches necessitate tools delivered to the nucleus, whereas inhibitors of NMD may act both in the nucleoplasm as well as the cytoplasm. Readthrough inducers modulate translation in the cytoplasm by interacting with the ribosome–mRNA complex.
Figure 2. Exon skipping of a PTC‐bearing exon (exon ) may be mediated by antisense oligoribonucleotides (AON) designed to target the pre‐mRNA splicing machinery (spliceosome) and to redirect splicing between exons − 1 and + 1, while maintaining the open reading frame, thereby allowing synthesis of an internally deleted protein, at least partially functional. The ‘normal’ splicing events are indicated as broken lines about the diagram.
Figure 3. General rules of nonsense‐mediated mRNA decay (NMD). When a ribosome is stopped prematurely at a PTC located more than 50–55 nucleotides upstream of the last exon–exon junction, the mRNA transcript is targeted for decay by the NMD pathway. Indeed, in mammalian cells, mRNA processing results in the insertion of multiprotein exon junctional complexes (EJCs) at splice sites of mature transcripts. This complex contains at least six proteins, including Y14, RNA export factor (REF) and TAP (mRNA transport‐associated protein)‐15. Then, it recruits Upf3, a nucleocytoplasmic shuttling factor, and Upf2, a perinuclear protein, both of which are involved in NMD. When translation terminates sufficiently upstream of an EJC, Upf1 which could be recruited to the mRNA by either translation release factors (eRFs) or Upf2, interacts with Upf2, becomes phosphorylated by Smg‐1 and bridges the terminated ribosome and the downstream EJC to form an active NMD complex that triggers rapid decay of the mRNA. This degradation involves decapping followed by 5′–3′ decay as well as deadenylation followed by 3′–5′ decay. Further studies are needed to better understand how the active NMD complex stimulates the RNA degradation machinery.
Figure 4. (a) Translational termination and readthrough. When a stop codon enters the A‐site of the ribosome, the efficiency of translation termination depends on the competition between recognition of the stop codon by release factors and decoding by a near‐cognate tRNA that can pair with two out of the three bases of the stop codon. Aminoglycosides belong to a large family of structurally related antibiotics. They can interact with the A‐site of the ribosome and induce readthrough by mimicking the conformational change in the 18S rRNA that would be induced by a correct codon–anticodon pair, thereby promoting near‐cognate tRNA incorporation. (b) Readthrough during pioneer round of translation may antagonise NMD. In the presence of a drug inducing translational readthrough during the pioneer round of translation, all EJCs are removed by the translating ribosomes. Then, the mRNA is thought to be stabilised as is freed from the EJC interactions required to promote NMD (Figure), resulting in increased steady‐state transcript levels.
Figure 5. Comparison between basal and gentamicin‐induced readthrough levels for 70 nonsense mutations involved in human disorders. Target sequences corresponding to individual nonsense mutations identified in patients and embedded in their original nucleotide context were inserted in a dual gene reporter system already described. These constructs have been used to quantify basal and gentamicin‐induced readthrough after transfection of mouse NIH3T3 cells (Bidou ., ). These results first illustrated that UGA or UAG stop mutations show, on average, higher translational readthrough than those with a UAA stop codon. This is consistent with the relative termination efficiency previously described for the three stop codons (UAA > UAG > UGA). Nevertheless, in the presence or absence of gentamicin, this order might be completely changed owing to the influence of the surrounding stop codon context. Indeed, some of the UAG mutations in less‐favoured contexts exhibit equivalent or even lower readthrough levels than those displayed by UAA mutations surrounded by leakier sequences. Notably, the impact of the first nucleotide after the stop codon, although important, is in fact largely dependent on the surrounding context. This study also highlights that a very broad variation is observed in both basal and gentamicin‐induced readthrough efficiency, depending on the mutation tested. Moreover, no correlation was found between the basal readthrough efficiency and the increase factor that reflects the responsiveness to the antibiotic. Indeed, only a minority of PTC detected in patients shows a significant level of gentamicin‐induced readthrough and would thus be amenable to this pharmacological treatment.


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Further Reading

Frischmeyer PA and Dietz HC (1999) Nonsense‐mediated mRNA decay in health and disease. Human Molecular Genetics 8: 1893–1900.

Kuzmiak HA and Maquat LE (2006) Applying nonsense‐mediated mRNA decay research to the clinic: progress and challenges. Trends in Molecular Medicine 12: 306–316.

Maquat LE and Carmichael GG (2001) Quality control of mRNA function. Cell 104: 173–176.

Mitrpant C, Fletcher S and Wilton SD (2009) Personalised genetic intervention for Duchenne muscular dystrophy: antisense oligomers and exon skipping. Current Molecular Pharmacology 2: 110–121.

Muir LA and Chamberlain JS (2009) Emerging strategies for cell and gene therapy of the muscular dystrophies. Expert Reviews in Molecular Medicine 11: e18. DOI: 10.1017/S1462399409001100.

Zingman LV, Park S, Olson TM, Alekseev AE and Terzic A (2007) Aminoglycoside‐induced translational read‐through in disease: overcoming nonsense mutations by pharmacogenetic therapy. Clinical Pharmacology & Therapeutics 81: 99–103.

Web Links

British Muscular Dystrophy Campaign website. http://www.muscular‐

Human Gene Mutation Database (HGMD).

Online Mendelian Inheritance in Man. A catalog of human genes and genetic disorders.

The Journal of Gene Medicine Clinical Trial site.

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Bidou, Laure, and Allamand, Valérie(Apr 2018) Nonsense Mutations Causing Inherited Diseases: Therapeutic Approaches. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022433.pub2]