Elsevier

Mutation Research/Reviews in Mutation Research

Volume 762, October–December 2014, Pages 52-64
Mutation Research/Reviews in Mutation Research

Review
Nonsense-mediated decay in genetic disease: Friend or foe?

https://doi.org/10.1016/j.mrrev.2014.05.001Get rights and content

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.

Introduction

According to the National Organization for Rare Disorders (NORD), there are nearly 7000 known rare genetic disorders. In the US, there are approximately 30 million people who have a genetic disorder, of which approximately 30% arise as a consequence of a nonsense or frameshift mutation that introduces a premature termination codon (PTC, also called a nonsense codon or premature stop codon) [1], [2]. Nonsense mutations in particular account for 20.3% of all disease-associated single-base pair mutations, and are three times more likely to come to clinical attention than missense mutations [3], [4]. These mutations commonly inactivate gene function due to the production of truncated protein products, as well as leading to a significant decrease in cytoplasmic mRNA abundance due to targeted degradation by nonsense-mediated mRNA decay (NMD).

NMD is an evolutionarily conserved translation-dependent mechanism in all eukaryotes that is responsible for recognizing and eliminating aberrant messenger RNA (mRNA) transcripts to prevent the production of truncated peptides that could have toxic and detrimental effects on the cell [5], [6], [7], [8], [9]. NMD plays a critical role in preventing the potential dominant-negative effect of non-functional protein within the cell, as well as the prevention of misfolded protein accumulation and subsequent initiation of the ER stress response. NMD primarily protects the cell against the deleterious effects of PTCs, but there is a growing body of evidence that mutation-, codon-, gene-, cell-, and tissue-specific differences in NMD efficiency can alter the underlying disease pathology [2], [10], [11], [12]. In fact, there is evidence that in certain genetic disorders, NMD can act to aggravate disease pathology and worsen the clinical phenotype, because degradation of the mutated mRNA prevents translation and accumulation of truncated peptides that retain residual activity [9], [10], [11]. In addition, there is evidence that inter-individual variability in NMD efficiency leads to differences in disease presentation and therapeutic outcome [13]. Therefore, NMD has emerged as a potent modulator of disease severity and clinical phenotype in light of its important role in recognizing and degrading mutated transcripts. The variable involvement of NMD in genetic disease has important implications for therapy, including decreased efficacy of read-through compounds intended to suppress the effects of nonsense mutations. In this review, we summarize current evidence that shows how NMD can modulate genetic disease pathology, why variability in NMD efficiency is important, and how NMD can be used as a therapeutic target.

Section snippets

Mechanism of substrate recognition and degradation

Eukaryotic cells contain a number of RNA quality control mechanisms to ensure the high fidelity of genetic expression, which protects the cell against the accumulation of nonfunctional RNA and the production of abnormal peptides [14]. mRNAs are largely responsible for protein production, and mRNA quality control is particularly important for protecting the cell against the harmful effects of genetic mutations. The synthesis and processing of mRNA involves transcription, capping, splicing,

Regulation of nonsense-mediated decay

In addition to RNA quality control, NMD acts as an RNA regulatory pathway that broadly controls approximately 10% of all cellular mRNAs in a wide variety of eukaryotes [24], [29], [30], and also acts as an important regulator of mRNA splicing [31], [32]. The dual role that NMD plays in RNA quality control and regulation of normal mRNA expression means NMD itself is under tight regulatory control. There are a number of examples in which NMD is inhibited by environmental insults, such as hypoxia,

Nonsense-mediated decay and genetic disease

Variable regulation of NMD factors leads to transcript-, cell-, and tissue-specific differences in NMD efficiency and modulates the manifestation and clinical severity of a number of genetic disorders in at least three major ways: (1) altering the pattern of inheritance, (2) causing distinct traits to manifest from mutations in the same gene, and (3) modifying the specific clinical phenotype [10]. There are many examples where NMD plays a significant role in the manifestation of human genetic

Nonsense suppression

The recognition of sense codons during translation is facilitated when aminoacyl-tRNAs enter the A site of the ribosome and sample the codon until a cognate aminoacyl-tRNA can bind. A cognate aminoacyl-tRNA has an anticodon sequence that can correctly pair with all three nucleotides of the A site codon. A proofreading step then occurs to confirm the correct codon–anticodon pairing and the cognate aminoacyl-tRNA becomes fully accommodated into the A site. This is followed by peptide bond

Conclusion and future outlook

Although NMD primarily acts to protect the cell from the downstream effects of nonsense mutations within the genome, there are many variables that act to undermine the potential benefit of this evolutionarily conserved mechanism. The dynamics of NMD regulation and the mutation-, codon-, gene-, cell-, and tissue-specific differences in NMD efficiency can alter the underlying disease pathology, which leads to different patterns of inheritance (autosomal recessive versus autosomal dominant), as

Conflict of interest statement

The authors declare no conflict of interest.

Funding

Partially supported by NIH R01NS43310 and the Beat Batten Foundation.

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