Nonsense-mediated mRNA decay: inter-individual variability and human disease.
Nonsense-mediated mRNA decay (NMD) is a regulatory pathway that functions to degrade transcripts containing premature termination codons (PTCs) and to maintain normal transcriptome homeostasis. Nonsense and frameshift mutations that generate PTCs cause approximately one-third of all known human genetic diseases and thus NMD has a potentially important role in human disease. In genetic disorders in which the affected genes carry PTC-generating mutations, NMD acts as a double-edge sword. While it can benefit the patient by degrading PTC-containing mRNAs that encode detrimental, dominant-negative truncated proteins, it can also make the disease worse when a PTC-containing mRNA is degraded that encodes a mutant but still functional protein. There is evidence that the magnitude of NMD varies between individuals, which, in turn, has been shown to correlate with both clinical presentations and the patients' responses to drugs that promote read-through of PTCs. In this review, we examine the evidence supporting the existence of inter-individual variability in NMD efficiency and discuss the genetic factors that underlie this variability. We propose that inter-individual variability in NMD efficiency is a common phenomenon in human populations and that an individual's NMD efficiency should be taken into consideration when testing, developing, and making therapeutic decisions for diseases caused by genes harboring PTCs.
School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA 5006, Australia.
Lam Son
LS
Nguyen
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093-0695, USA; Institute of Genomic Medicine, University of California, San Diego, USA.
Miles F
MF
Wilkinson
School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA 5006, Australia; Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA 5006, Australia. Electronic address: jozef.gecz@adelaide.edu.au.
Jozef
J
Gecz
D000818:Animals; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D059365:Nonsense Mediated mRNA Decay / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics
Copy number variation; Expression quantitative trait loci; Inter-individual NMD efficiency; Nonsense-mediated mRNA decay; Regulation of NMD; Staufen-mediated mRNA decay; miR-125; miR-128