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.

VariantASGR1Associated with a Reduced Risk of Coronary Artery Disease

“…21 However, since one third of the ASGR1 transcripts in heterozygous carriers had the 22-bp frameshift deletion, these transcripts are not fully eliminated by this process. If translated, the variant ASGR1 transcript would be predicted to generate a truncated protein (Fig.…”

Genetic analyses of novel compound heterozygous hypodysfibrinogenemia, Tsukuba I: FGG c.1129+62_65 del AATA and FGG c.1299+4 del A

“…However, we did not observe the shortened length of the -chain for the patient's fibrinogen; therefore, this aberrant -chain may not exist in plasma. These results suggest that aberrant -chain mRNA possessing the premature termination codon at 363 is destroyed in hepatocytes, most likely through nonsense-mediated mRNA decay [16,17]. In addition, the minigene incorporating the IVS-8 deletion partially produced a normal splicing product, but at a lower amount than that of the aberrant product.…”

A Novel Single-Nucleotide Deletion (c.1020delA) in NSUN2 Causes Intellectual Disability in an Emirati Child

“…It has been estimated that one third of genetic diseases are caused by nonsense or frameshift mutations that introduce premature termination codons (Frischmeyer and Dietz 1999). These mutations result in truncated proteins with a significant decrease in mRNA level due to NMD degradation (Miller et al 2014). To elucidate the effect of this deletion, relative expression of NSUN2 transcripts was performed in our patient and healthy control sample.…”