Abstract
It is estimated that one-third of disease-causing mutations may induce aberrant splicing of pre-messenger RNA transcripts and a partially overlapping third to premature stop codons (PTC) and nonsense-mediated mRNA decay (NMD). In some diseases, the estimate even goes up to 50% and >70%, respectively. These highly prevalent effects of different mutations on mRNA processing have prompted much effort for the identification of compounds towards the therapy of a substantial number of diseases with mutation-specific, personalized medicine. Here I review the widespread occurrence of aberrant splicing, NMD and their association in human genetic diseases, and discuss the rationales underlying the corresponding therapeutic strategies and challenges. The ability to sequence and analyze the human genome and transcriptomes of various sources at speeds unimaginable more than 20 years ago has had huge impacts on not only basic biological research but also the development of novel therapeutic strategies for human genetic diseases. Particularly this ability allows the screening of mutations in individuals at a genome/transcriptome scale for the design of different therapeutic strategies for mutation-specific, personalized medicine based on how the mutations take their toll. For the genetic information-based disease therapy, RNA has also been targeted besides DNA and protein, with an accelerating speed of research in recent years. This development has mainly benefited from our understanding of different aspects of RNA processing and appreciation of their prevalence, such as the widespread presence of alternative pre-mRNA splicing in human transcriptomes, mRNA quality control by nonsense-mediated decay (NMD), as well as microRNA, long noncoding RNA and other non-coding RNAs. Their misregulation due to mutations has been linked to or associated with the development of human genetic diseases. Here I will discuss the therapeutic potential of targeting aberrant splicing and NMD, two widespread and related effects of a large number of genetic mutations that cause human diseases.
Highlights
nonsense-mediated mRNA decay (NMD) induced by aberrant splicing premature stop codons (PTC)In total (A+B), about 70% PTC/NMD in the ATM and NF1 mutant transcripts examined. percentages are close to or more than 70% (14 of 21; 10 of 14; 24 of 29) in three studies [40,41,42]
It is estimated that one-third of disease-causing mutations may induce aberrant splicing of pre-messenger RNA transcripts and a partially overlapping third to premature stop codons (PTC) and nonsense-mediated mRNA decay (NMD)
This development has mainly benefited from our understanding of different aspects of RNA processing and appreciation of their prevalence, such as the widespread presence of alternative pre-mRNA splicing in human transcriptomes, mRNA quality control by nonsense-mediated decay (NMD), as well as microRNA, long noncoding RNA and other non-coding RNAs
Summary
In total (A+B), about 70% PTC/NMD in the ATM and NF1 mutant transcripts examined. percentages are close to or more than 70% (14 of 21; 10 of 14; 24 of 29) in three studies [40,41,42]. In an exhaustive analysis 54 of the 62 mutations (87%) of the NF1 gene cause protein truncation within the first 42 of the 46 exons examined [43], due to nonsense, missense, insertion, deletion or splice mutations. Overall, these four independent NF1 studies point to an average of 77% (±8.3) mutations that cause NMD. For aberrant splicing-caused NMD, it could be due to mutations of either the cis-acting elements or trans-acting splice factors The latter could result in the NMD of a group of transcripts. The high prevalence of aberrant splicing and NMD among disease gene transcripts and their association with each other
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