Nonsense-mediated mRNA decay: Inter-individual variability and human disease

Lam Son Nguyen, Miles F. Wilkinson, Jozef Gecz

Research output: Contribution to journalReview article

63 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)175-186
Number of pages12
JournalNeuroscience and Biobehavioral Reviews
Issue numberP2
Publication statusPublished - 1 Oct 2014
Externally publishedYes


  • Copy number variation
  • Expression quantitative trait loci
  • Inter-individual NMD efficiency
  • MiR-125
  • MiR-128
  • Nonsense-mediated mRNA decay
  • Regulation of NMD
  • Staufen-mediated mRNA decay

ASJC Scopus subject areas

  • Neuropsychology and Physiological Psychology
  • Cognitive Neuroscience
  • Behavioral Neuroscience

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