Heritability in the Efficiency of Nonsense-Mediated mRNA Decay in Humans

Abstract

BackgroundIn eukaryotes mRNA transcripts of protein-coding genes in which an intron has been retained in the coding region normally result in premature stop codons and are therefore degraded through the nonsense-mediated mRNA decay (NMD) pathway. There is evidence in the form of selective pressure for in-frame stop codons in introns and a depletion of length three introns that this is an important and conserved quality-control mechanism. Yet recent reports have revealed that the efficiency of NMD varies across tissues and between individuals, with important clinical consequences.Principal FindingsUsing previously published Affymetrix exon microarray data from cell lines genotyped as part of the International HapMap project, we investigated whether there are heritable, inter-individual differences in the abundance of intron-containing transcripts, potentially reflecting differences in the efficiency of NMD. We identified intronic probesets using EST data and report evidence of heritability in the extent of intron expression in 56 HapMap trios. We also used a genome-wide association approach to identify genetic markers associated with intron expression. Among the top candidates was a SNP in the DCP1A gene, which forms part of the decapping complex, involved in NMD.ConclusionsWhile we caution that some of the apparent inter-individual difference in intron expression may be attributable to different handling or treatments of cell lines, we hypothesize that there is significant polymorphism in the process of NMD, resulting in heritable differences in the abundance of intronic mRNA. Part of this phenotype is likely to be due to a polymorphism in a decapping enzyme on human chromosome 3.

Functional analysis of splicing mutations in the IDS gene and the use of antisense oligonucleotides to exploit an alternative therapy for MPS II

“…However, there is growing evidence that mutation, codon, gene, cell and tissue-specific differences in NMD efficiency can alter the underlying disease pathology. Moreover, inter-individual variation in NMD efficiency among patients carrying identical mutations have also been reported [41,42]. The differences in the NMD mechanism activation here observed between two transcripts having PTCs could be explained by this recent data.…”

Intellectual ability in tuberous sclerosis complex correlates with predicted effects of mutations on TSC1 and TSC2 proteins

“…These factors include somatic mosaicism,51 modifier genes (perhaps affecting NMD efficiency)52 and environmental effects such as seizures28 (although tubers and seizures combined accounted for only 47% of the variance in IQ in the study of O'Callaghan et al 16). Nevertheless, it is clear that there are differing effects of distinct mutations in TSC1 and TSC2 (and specific mutations associated with a mild phenotype have been recognised for some time, e.g.…”

Therapeutics Based on Stop Codon Readthrough

“…The efficiency of the NMD pathway, which plays an important role in modulating the phenotypes of diseases caused by PTCs, varies by as much as fourfold among the general population (77, 124, 137). Importantly, these differences in NMD efficiency influence the inheritance pattern and modulate the clinical severity of numerous disorders (12, 70), possibly because of changes in residual mRNA abundance that influence the levels of truncated protein (or full-length protein produced by basal PTC readthrough).…”