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 n) may be mediated by antisense oligoribonucleotides (AON) designed to target the pre‐mRNA splicing machinery (spliceosome) and to redirect splicing between exons n − 1 and n + 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 et al., ). 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.


Aartsma‐Rus A and Krieg AM (2017) FDA approves Eteplirsen for Duchenne Muscular Dystrophy: the next chapter in the Eteplirsen Saga. Nucleic Acid Therapeutics 27 (1): 1–3.

Aartsma‐Rus A, Straub V, Hemmings R, et al. (2017) Development of exon skipping therapies for Duchenne Muscular Dystrophy: a critical review and a perspective on the outstanding issues. Nucleic Acid Therapeutics 27 (5): 251–259.

Allamand V, Bidou L, Arakawa M, et al. (2008) Drug induced readthrough of premature stop codons leads to the stabilization of laminin a2 chain mRNA in CMD myotubes. Journal of Gene Medicine 10: 217–224.

Arakawa M, Nakayama Y, Hara T, et al. (2001) Negamycin can restore dystrophin in mdx skeletal muscle. Acta Myologica 20: 154–158.

Atanasova VS, Jiang Q, Prisco M, et al. (2017) Amlexanox enhances premature termination codon read‐through in COL7A1 and expression of full length type VII collagen: potential therapy for recessive dystrophic epidermolysis bullosa. Journal of Investigative Dermatology 137 (9): 1842–1849.

Auld DS, Lovell S, Thorne N, et al. (2010) Molecular basis for the high‐affinity binding and stabilization of firefly luciferase by PTC124. Proceedings of the National Academy of Sciences of the United States of America 107: 4878–4883.

Baradaran‐Heravi A, Balgi AD, et al. (2016) Novel small molecules potentiate premature termination codon readthrough by aminoglycosides. Nucleic Acids Research 44 (14): 6583–6598.

Baradaran‐Heravi A, Niesser J, et al. (2017) Gentamicin B1 is a minor gentamicin component with major nonsense mutation suppression activity. Proceedings of the National Academy of Sciences of the United States of America 114 (13): 3479–3484.

Barton‐Davis ER, Cordier L, Shoturma DI, Leland SE and Sweeney HL (1999) Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. Journal of Clinical Investigation 104: 375–381.

Bateman JF, Freddi S, Nattrass G and Savarirayan R (2003) Tissue‐specific RNA surveillance? Nonsense‐mediated mRNA decay causes collagen X haploinsufficiency in Schmid metaphyseal chondrodysplasia cartilage. Human Molecular Genetics 12: 217–225.

Bedwell DM, Kaenjak A, Benos DJ, et al. (1997) Suppression of a CFTR premature stop mutation in a bronchial epithelial cell line. Nature Medicine 3: 1280–1284.

Bidou L, Hatin I, Perez N, et al. (2004) Premature stop codons involved in muscular dystrophies show a broad spectrum of readthrough efficiencies in response to gentamicin treatment. Gene Therapy 11: 619–627.

Bidou L, Bugaud O, et al. (2017) Characterization of new‐generation aminoglycoside promoting premature termination codon readthrough in cancer cells. RNA Biology 14 (3): 378–388.

Blanchet S, Cornu D, et al. (2014) New insights into the incorporation of natural suppressor tRNAs at stop codons in Saccharomyces cerevisiae. Nucleic Acids Research 42 (15): 10061–10072.

Bolze F, Mocek S, Zimmermann A, et al. (2017) Aminoglycosides, but not PTC124 (Ataluren), rescue nonsense mutations in the leptin receptor and in luciferase reporter genes. Scientific Reports 7 (1): 1020.

Bonetti B, Fu L, Moon J and Bedwell DM (1995) The efficiency of translation termination is determined by a synergistic interplay between upstream and downstream sequences in Saccharomyces cerevisiae. Journal of Molecular Biology 251: 334–345.

Bordeira‐Carrico R, Ferreira D, Mateus DD, et al. (2014) Rescue of wild‐type E‐cadherin expression from nonsense‐mutated cancer cells by a suppressor‐tRNA. European Journal of Human Genetics 22 (9): 1085–1092.

Brogna S and Wen J (2009) Nonsense‐mediated mRNA decay (NMD) mechanisms. Nature Structural and Molecular Biology 16: 107–113.

Brown A, Shao S, Murray J, et al. (2015) Structural basis for stop codon recognition in eukaryotes. Nature 524 (7566): 493–496.

Bruno IG, Karam R, Huang L, et al. (2011) Identification of a microRNA that activates gene expression by repressing nonsense‐mediated RNA decay. Molecular Cell 42 (4): 500–510.

Burke JF and Mogg AE (1985) Suppression of a nonsense mutation in mammalian cells in vivo by the aminoglycoside antibiotics G‐418 and paromomycin. Nucleic Acids Research 13: 6265–6272.

Buvoli M, Buvoli A and Leinwand LA (2000) Suppression of nonsense mutations in cell culture and mice by multimerized suppressor tRNA genes. Molecular and Cellular Biology 20 (9): 3116–3124.

Byers PH (2002) Killing the messenger: new insights into nonsense‐mediated mRNA decay. Journal of Clinical Investigation 109: 3–6.

Caspi M, Firsow A, Rajkumar R, et al. (2016) A flow cytometry‐based reporter assay identifies macrolide antibiotics as nonsense mutation read‐through agents. Journal of Molecular Medicine (Berlin, Germany) 94 (4): 469–482.

Chamberlain JR and Chamberlain JS (2017) Progress toward gene therapy for Duchenne muscular dystrophy. Molecular Therapy 25 (5): 1125–1131.

Chang YF, Imam JS and Wilkinson MF (2007) The nonsense‐mediated decay RNA surveillance pathway. Annual Review of Biochemistry 76: 51–74.

Conti E and Izaurralde E (2005) Nonsense‐mediated mRNA decay: molecular insights and mechanistic variations across species. Current Opinion in Cell Biology 17: 316–325.

Dabrowski M, Bukowy‐Bieryllo Z and Zietkiewicz E (2015) Translational readthrough potential of natural termination codons in eucaryotes – The impact of RNA sequence. RNA Biology 12 (9): 950–958.

Demir E, Sabatelli P, Allamand V, et al. (2002) Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy. American Journal of Human Genetics 70: 1446–1458.

Dietz HC, Valle D, Francomano CA, et al. (1993) The skipping of constitutive exons in vivo induced by nonsense mutations. Science 259: 680–683.

Dominski Z and Kole R (1993) Restoration of correct splicing in thalassemic pre‐mRNA by antisense oligonucleotides. Proceedings of the National Academy of Sciences of the United States of America 90: 8673–8677.

Du M, Keeling KM, Fan L, et al. (2006) Clinical doses of amikacin provide more effective suppression of the human CFTR‐G542X stop mutation than gentamicin in a transgenic CF mouse model. Journal of Molecular Medicine 84: 573–582.

Du L, Damoiseaux R, Nahas S, et al. (2009) Nonaminoglycoside compounds induce readthrough of nonsense mutations. The Journal of Experimental Medicine 206: 2285–2297.

Durand S, Cougot N, Mahuteau‐Betzer F, et al. (2007) Inhibition of nonsense‐mediated mRNA decay (NMD) by a new chemical molecule reveals the dynamic of NMD factors in P‐bodies. The Journal of Cell Biology 178: 1145–1160.

Finkel RS, Chiriboga CA, Valjar J, et al. (2016) Treatment of infantile‐onset spinal muscular atrophy with nusinersen: a phase 2, open‐label, dose‐escalation study. Lancet 388 (10063): 3017–3026.

Finkel RS, Mercuri E, Darras BT, et al. (2017) Nusinersen versus Sham control in infantile‐onset spinal muscular atrophy. New England Journal of Medicine 377 (18): 1723–1732.

Floquet C, Deforges J, Rousset JP, et al. (2011) Rescue of non‐sense mutated p53 tumor suppressor gene by aminoglycosides. Nucleic Acids Research 39 (8): 3350–3362.

Floquet C, Hatin I, Rousset JP, et al. (2012) Statistical analysis of readthrough levels for nonsense mutations in mammalian cells reveals a major determinant of response to gentamicin. PLoS Genetics 8 (3): e1002608.

Gonzalez‐Hilarion S, Beghyn T, Jia J, et al. (2012) Rescue of nonsense mutations by amlexanox in human cells. Orphanet Journal of Rare Diseases 7: 58.

Hentze MW and Kulozik AE (1999) A perfect message: RNA surveillance and nonsense‐mediated decay. Cell 96: 307–310.

Hoy SM (2017) Nusinersen: first global approval. Drugs 77 (4): 473–479.

Inoue K, Khajavi M, Ohyama T, et al. (2004) Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nature Genetics 36: 361–369.

Isken O and Maquat LE (2007) Quality control of eukaryotic mRNA: safeguarding cells from abnormal mRNA function. Genes & Development 21: 1833–3856.

Jin Y, Zhang F, Ma Z, et al. (2016) MicroRNA 433 regulates nonsense‐mediated mRNA decay by targeting SMG5 mRNA. BMC Molecular Biology 17 (1): 17.

Kannan K, Kanabar P, Schryer D, et al. (2014) The general mode of translation inhibition by macrolide antibiotics. Proceedings of the National Academy of Sciences of the United States of America 111 (45): 15958–15963.

Kayali R, Ku JM, Khitrov G, et al. (2012) Read‐through compound 13 restores dystrophin expression and improves muscle function in the mdx mouse model for Duchenne muscular dystrophy. Human Molecular Genetics 21 (18): 4007–4020.

Keeling KM, Brooks DA, Hopwood JJ, et al. (2001) Gentamicin‐mediated suppression of Hurler syndrome stop mutations restores a low level of {{alpha}}‐L‐iduronidase activity and reduces lysosomal glycosaminoglycan accumulation. Human Molecular Genetics 10 (3): 291–299.

Keeling KM, Lanier J, Du M, et al. (2004) Leaky termination at premature stop codons antagonize nonsense‐mediated mRNA decay in S. cerevisiae. RNA 10: 691–703.

Keeling KM, Wang D, Dai Y, et al. (2013) Attenuation of nonsense‐mediated mRNA decay enhances in vivo nonsense suppression. PLoS ONE 8 (4): e60478.

Keeling KM, Xue X, Gunn G, et al. (2014) Therapeutics based on stop codon readthrough. Annual Review of Genomics and Human Genetics 15: 371–394.

Kerem E, Hirawat S, Armoni S, et al. (2008) Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet 372: 719–727.

Kiselev A, Ostapenko O, Rogozhkina E, et al. (2002) Suppression of nonsense mutations in the dystrophin gene by a suppressor tRNA gene. Molekuliarnaia Biologiia 36: 43–47.

Kurosaki T and Maquat LE (2016) Nonsense‐mediated mRNA decay in humans at a glance. Journal of Cell Science 129 (3): 461–467.

Labunskyy VM, Hatfield DL and Gladyshev VN (2014) Selenoproteins: molecular pathways and physiological roles. Physiological Reviews 94 (3): 739–777.

Le Guiner C, Montus M, Servais L, et al. (2014) Forelimb treatment in a large cohort of dystrophic dogs supports delivery of a recombinant AAV for exon skipping in Duchenne patients. Molecular Therapy 22 (11): 1923–1935.

Lim KR, Maruyama R and Yokota T (2017) Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Design, Development and Therapy 11: 533–545.

Linde L, Boelz S, Nissim‐Rafinia M, et al. (2007) Nonsense‐mediated mRNA decay affects nonsense transcript levels and governs response of cystic fibrosis patients to gentamicin. The Journal of Clinical Investigation 117: 683–692.

Lykke‐Andersen S and Jensen TH (2015) Nonsense‐mediated mRNA decay: an intricate machinery that shapes transcriptomes. Nature Reviews Molecular Cell Biology 16 (11): 665–677.

Malik V, Rodino‐Klapac LR, Viollet L, et al. (2010) Gentamicin‐induced readthrough of stop codons in Duchenne muscular dystrophy. Annals of Neurology 67 (6): 771–780.

Manuvakhova M, Keeling K and Bedwell DM (2000) Aminoglycoside antibiotics mediate context‐dependent suppression of termination codons in a mammalian translation system. RNA 6: 1044–1055.

McDonald CM, Campbell C, Torricelli RE, et al. (2017) Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double‐blind, placebo‐controlled, phase 3 trial. Lancet 390 (10101): 1489–1498.

Metzstein MM and Krasnow MA (2006) Functions of the nonsense‐mediated mRNA decay pathway in Drosophila development. PLoS Genetics 2: e180.

Mort M, Ivanov D, Cooper D and Chuzhanova N (2008) A meta‐analysis of nonsense mutations causing human genetic disease. Human Mutation 29: 1037–1047.

Moulton HM and Moulton JD (2010) Morpholinos and their peptide conjugates: therapeutic promise and challenge for Duchenne muscular dystrophy. Biochimica et Biophysica Acta. DOI: 10.1016/j.bbamem.2010.02.012.

Mutyam V, Du M, Xue X, et al. (2016) Discovery of clinically approved agents that promote suppression of cystic fibrosis transmembrane conductance regulator nonsense mutations. American Journal of Respiratory and Critical Care Medicine 194 (9): 1092–1103.

Namy O, Hatin I and Rousset JP (2001) Impact of the six nucleotides downstream of the stop codon on translation termination. EMBO Reports 2 (9): 787–793.

Neu‐Yilik G, Raimondeau E, Eliseev B, et al. (2017) Dual function of UPF3B in early and late translation termination. EMBO Journal 36 (20): 2968–2986.

Nickless A Bailis JM and You Z (2017) Control of gene expression through the nonsense‐mediated RNA decay pathway. Cell & Bioscience 7: 26.

Nomakuchi TT, Rigo F, Aznarez I, et al. (2016) Antisense oligonucleotide‐directed inhibition of nonsense‐mediated mRNA decay. Nature Biotechnology 34 (2): 164–166.

Nudelman I, Rebibo‐Sabbah A, Cherniavsky M, et al. (2009) Development of novel aminoglycoside (NB54) with reduced toxicity and enhanced suppression of disease‐causing premature stop mutations. Journal of Medicinal Chemistry 52: 2836–2845.

Osman EY, Washington CW, Simon ME, et al. (2017) Analysis of azithromycin monohydrate as a single or a combinatorial therapy in a mouse model of severe spinal muscular atrophy. Journal of Neuromuscular Diseases 4 (3): 237–249.

Palmer E, Wilhelm JM and Sherman F (1979) Phenotypic suppression of nonsense mutants in yeast by aminoglycoside antibiotics. Nature 277: 148–150.

Ramakrishnan V (2002) Ribosome structure and the mechanism of translation. Cell 108: 557–572.

Rederstorff M, Allamand V, Guicheney P, et al. (2008) Ex vivo correction of selenoprotein N deficiency in rigid spine muscular dystrophy caused by a mutation in the selenocysteine codon. Nucleic Acids Research 36: 237–244.

Roy B, Leszyk JD, Mangus DA, et al. (2015) Nonsense suppression by near‐cognate tRNAs employs alternative base pairing at codon positions 1 and 3. Proceedings of the National Academy of Sciences of the United States of America 112 (10): 3038–3043.

Roy B, Friesen WJ, Tomizawa Y, et al. (2016) Ataluren stimulates ribosomal selection of near‐cognate tRNAs to promote nonsense suppression. Proceedings of the National Academy of Sciences of the United States of America 113 (44): 12508–12513.

Sangkuhl K, Schulz A, Rompler H, et al. (2004) Aminoglycoside‐mediated rescue of a disease‐causing nonsense mutation in the V2 vasopressin receptor gene in vitro and in vivo. Human Molecular Genetics 13 (9): 893–903.

Sermet‐Gaudelus I, Renouil M, Fajac A, et al. (2007) In vitro prediction of stop‐codon suppression by intravenous gentamicin in patients with cystic fibrosis: a pilot study. BMC Medicine 5: 5.

Shulman E, Belakhov V, Wei G, et al. (2014) Designer aminoglycosides that selectively inhibit cytoplasmic rather than mitochondrial ribosomes show decreased ototoxicity: a strategy for the treatment of genetic diseases. Journal of Biological Chemistry 289 (4): 2318–2330.

Sossi V, Giuli A, Vitali T, et al. (2001) Premature termination mutations in exon 3 of the SMN1 gene are associated with exon skipping and a relatively mild SMA phenotype. European Journal of Human Genetics 9: 113–120.

Tauris J, Christensen EI, Nykjaer A, et al. (2009) Cubilin and megalin co‐localize in the neonatal inner ear. Audiology & Neuro‐Otology 14 (4): 267–278.

Temple G, Dozy A, Roy K and Kan Y (1982) Construction of a functional human suppressor tRNA gene: an approach to gene therapy for beta‐thalassaemia. Nature 296: 537–540.

Usuki F, Yamashita A, Kashima I, et al. (2006) Specific inhibition of nonsense‐mediated mRNA decay components, SMG‐1 or Upf1, rescues the phenotype of ullrich disease fibroblasts. Molecular Therapy 14: 351–360.

Usuki F, Yamashita A, Shiraishi T, et al. (2013) Inhibition of SMG‐8, a subunit of SMG‐1 kinase, ameliorates nonsense‐mediated mRNA decay‐exacerbated mutant phenotypes without cytotoxicity. Proceedings of the National Academy of Sciences of the United States of America 110 (37): 15037–15042.

Wan L and Dreyfuss G (2017) Splicing‐correcting therapy for SMA. Cell 170 (1): 5.

Wang G, Jiang B, Jia C, et al. (2013) MicroRNA 125 represses nonsense‐mediated mRNA decay by regulating SMG1 expression. Biochemical and Biophysical Research Communications 435 (1): 16–20.

Wang G, Chai B and Yang L, et al. (2016) MiR‐128 and miR‐125 regulate expression of coagulation Factor IX gene with nonsense mutation by repressing nonsense‐mediated mRNA decay. Biomedicine and Pharmacotherapy 80: 331–337.

Welch EM, Barton ER, Zhuo J, et al. (2007) PTC124 targets genetic disorders caused by nonsense mutations. Nature 447: 87–91.

Wilton SD, Dye DE, Blechynden LM and Laing NG (1997) Revertant fibres: a possible genetic therapy for Duchenne muscular dystrophy? Neuromuscular Disorders 7: 329–335.

Wittkopp N, Huntzinger E, Weiler C, et al. (2009) Nonsense‐mediated mRNA decay effectors are essential for zebrafish embryonic development and survival. Molecular and Cellular Biology 29: 3517–3528.

Wittmann J, Hol EM and Jäck H‐M (2006) hUPF2 silencing identifies physiologic substrates of mammalian nonsense‐mediated mRNA decay. Molecular and Cellular Biology 26: 1272–1287.

Woodley DT, Cogan J, Hou Y, et al. (2017) Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients. Journal of Clinical Investigation 127 (8): 3028–3038.

Xue X, Mutyam V, Tang L, et al. (2014) Synthetic aminoglycosides efficiently suppress cystic fibrosis transmembrane conductance regulator nonsense mutations and are enhanced by ivacaftor. American Journal of Respiratory Cell and Molecular Biology 50 (4): 805–816.

Xue X, Mutyam V, Thakerar A, et al. (2017) Identification of the amino acids inserted during suppression of CFTR nonsense mutations and determination of their functional consequences. Human Molecular Genetics 26 (16): 3116–3129.

Zhao Y, Lin J, Xu B, et al. (2014) MicroRNA‐mediated repression of nonsense mRNAs. eLife 3: e03032.

Zilberberg A, Lahav L and Rosin‐Arbesfeld R (2010) Restoration of APC gene function in colorectal cancer cells by aminoglycoside‐ and macrolide‐induced read‐through of premature termination codons. Gut 59: 496–507.

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]