title: Nonsense-mediated decay in genetic disease: friend or foe?
abstract: Eukaryotic cells utilize various RNA quality control mechanisms to ensure high fidelity of gene expression, thus protecting against the accumulation of nonfunctional RNA and the subsequent production of abnormal peptides. Messenger RNAs (mRNAs) are largely responsible for protein production, and mRNA quality control is particularly important for protecting the cell against the downstream effects of genetic mutations. Nonsense-mediated decay (NMD) is an evolutionarily conserved mRNA quality control system in all eukaryotes that degrades transcripts containing premature termination codons (PTCs). By degrading these aberrant transcripts, NMD acts to prevent the production of truncated proteins that could otherwise harm the cell through various insults, such as dominant negative effects or the ER stress response. Although NMD functions to protect the cell against the deleterious effects of aberrant mRNA, there is a growing body of evidence that mutation-, codon-, gene-, cell-, and tissue-specific differences in NMD efficiency can alter the underlying pathology of genetic disease. In addition, the protective role that NMD plays in genetic disease can undermine current therapeutic strategies aimed at increasing the production of full-length functional protein from genes harboring nonsense mutations. Here, we review the normal function of this RNA surveillance pathway and how it is regulated, provide current evidence for the role that it plays in modulating genetic disease phenotypes, and how NMD can be used as a therapeutic target.
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD, USA; Sanford Children's Health Research Center, Sanford Research, Sioux Falls, SD, USA.
authors.forename: Jake N
authors.initials: JN
authors.lastname: Miller
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD, USA; Sanford Children's Health Research Center, Sanford Research, Sioux Falls, SD, USA; Department of Pediatrics, Sanford School of Medicine of the University of South Dakota, Sioux Falls, SD, USA. Electronic address: david.pearce@sanfordhealth.org.
authors.forename: David A
authors.initials: DA
authors.lastname: Pearce
mesh_terms: D000818:Animals; D004194:Disease / Q000145:classification / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D059365:Nonsense Mediated mRNA Decay; D009928:Organ Specificity; D012333:RNA, Messenger / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger
keywords: Genetic disease; Nonsense suppression; Nonsense-mediated decay; Read-through