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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: (i) the genomic deoxyribonucleic acid (DNA) by replacing the defective gene; (ii) 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 RNA (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 (PTC) 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 PTC 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

Coding sequences are defined between a start and a stop codon. The appearance of a nonsense mutation in a coding sequence creates a premature termination codon (PTC), preventing the correct production of the corresponding protein by interrupting translation and inducing the degradation of the transcript via the nonsense-mediated mRNA decay (NMD) pathway. Over the past 10 years, there has been considerable interest in the possibility of suppressing in-frame PTCs for therapeutic purposes. Indeed, some drugs have been shown to promote PTC readthrough by binding to mammalian ribosomes, thereby partially restoring the synthesis of a full-length protein in cultured mammalian cells and animal models. This translational suppression strategy represents a promising therapeutic approach for genetic diseases and cancers due to a PTC. Key Concepts The stop codons in humans are UAA, UAG and UGA, and they are recognised by release factors. Near-cognate tRNA-binding codons display base pairing for only two of the three bases of the codon. Stop codon readthrough is the process by which the ribosome incorporates a near-cognate tRNA at the stop codon. Keywords: stop codon readthrough; ribosome; translation; premature termination codon; genetic diseases