Lejeune, F. & Maquat, L. E. Mechanistic links between nonsense-mediated mRNA decay and pre-mRNA splicing in mammalian cells. Curr. Opin. Cell Biol. 17, 309-315

Department of Biochemistry and Biophysics, University of Rochester, School of Medicine and Dentistry, Rochester, New York, USA.
Current Opinion in Cell Biology (Impact Factor: 8.47). 07/2005; 17(3):309-15. DOI: 10.1016/
Source: PubMed


Nonsense-mediated mRNA decay (NMD) generally involves nonsense codon recognition by translating ribosomes at a position approximately 25 nts upstream of a splicing-generated exon junction complex of proteins. As such, NMD provides a means to degrade abnormal mRNAs that encode potentially deleterious truncated proteins. Additionally, an estimated one-third of naturally occurring, alternatively spliced mRNAs is also targeted for NMD. Given the extraordinary frequency of alternative splicing together with data indicating that naturally occurring transcripts other than alternatively spliced mRNAs are likewise targeted for NMD, it is believed that mammalian cells routinely utilize NMD to achieve proper levels of gene expression.

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Available from: Fabrice Lejeune
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    • "Missense mutations constitute about 42% of all EFNB1 mutations and lead to the exchange of amino acid residues that are important for receptor-ligand interaction and signaling (Twigg et al., 2004; Wieland et al., 2005). Truncating mutations are associated with extremely reduced transcript levels via a mechanism known as nonsense-mediated RNA decay that prevents the translation of transcripts carrying PTCs (Lejeune and Maquat, 2005). Only a minority of EFNB1 truncating or splice-site mutations have been investigated at the expression level (Makarov et al., 2010; Wieland et al., 2008). "
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    ABSTRACT: Craniofrontonasal syndrome (CFNS) is an X-linked disorder caused by mutations in the EFNB1 gene and characterized by distinctive craniofacial and digital malformations. In contrast with most X-linked traits, female patients with CFNS display a more severe phenotype than males. In this report, the clinical, molecular and RNA expression analyses of a female subject with CFNS are described. A novel c.445_449delGAGGG deletion in exon 3 of EFNB1 was demonstrated in this patient. To assess the effect of this novel mutation at the transcript level, the expression of EFNB1 mRNA was studied by quantitative RT-PCR. To our knowledge, this is the first time that an EFNB1 transcript carrying a truncating mutation in exon 3 is demonstrated to undergo degradation by nonsense-mediated mRNA decay. Our results expand the mutational spectrum of CFNS and add to the functional consequences of truncating EFNB1 mutations.
    Full-text · Article · Dec 2014 · Meta Gene
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    • "Alternative splicing in non-coding sequences, instead, can affect the efficiency of mRNA translation, stability or localization [26]. By modifying the reading frame or adding premature stop codons, some splicing events lead to truncated proteins or “Nonsense-Mediated mRNA Degradation” (NMD mechanism) [27]. In this manner, splicing works as an on–off switch in gene expression. "
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    ABSTRACT: The completion of the Human Genome Project aroused renewed interest in alternative splicing, an efficient and widespread mechanism that generates multiple protein isoforms from individual genes. Although our knowledge about alternative splicing is growing exponentially, its real impact on cellular life is still to be clarified. Connecting all splicing features (genes, splice transcripts, isoforms, and relative functions) may be useful to resolve this tangle. Herein, we will start from the case of a single gene, Parkinson protein 2, E3 ubiquitin protein ligase (PARK2), one of the largest in our genome. This gene is implicated in the pathogenesis of autosomal recessive juvenile Parkinsonism and it has been recently linked to cancer, leprosy, autism, type 2 diabetes mellitus and Alzheimer's disease. PARK2 primary transcript undergoes an extensive alternative splicing, which enhances transcriptomic diversification and protein diversity in tissues and cells. This review will provide an update of all human PARK2 alternative splice transcripts and isoforms presently known, and correlate them to those in rat and mouse, two common animal models for studying human disease genes. Alternative splicing relies upon a complex process that could be easily altered by both cis and trans-acting mutations. Although the contribution of PARK2 splicing in human disease remains to be fully explored, some evidences show disruption of this versatile form of genetic regulation may have pathological consequences.
    Full-text · Article · Jun 2014 · Current Genomics
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    • "One possibility could be that SPO11 is controlled in a precise way via the pathways of alternative splicing and non-sense mediated decay. The NMD pathway offer a mechanism which is routinely used by mammals and others to regulate gene expression (Lareau et al., 2004; Lejeune and Maquat, 2005). Such effects were observed for mice and men where the splicing of SPO11 and other meiosis specific genes are regulated during meiosis (Habu et al., 1996; Schmid et al., 2013). "
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    ABSTRACT: Toward the global understanding of plant meiosis, it seems to be essential to decipher why all as yet sequenced plants need or at least encode for two different meiotic SPO11 genes. This is in contrast to mammals and fungi, where only one SPO11 is present. Both SPO11 in Arabidopsis thaliana are essential for the initiation of double strand breaks (DSBs) during the meiotic prophase. In nearly all eukaryotic organisms DSB induction during prophase I by SPO11 leads to meiotic DSB repair, thereby ensuring the formation of a necessary number of crossovers (CO) as physical connections between the homologous chromosomes. We aim to investigate the specific functions and evolution of both SPO11 genes in land plants. Therefore, we identified and cloned the respective orthologous genes from Brassica rapa, Carica papaya, Oryza sativa, and Physcomitrella patens. In parallel we determined the full length cDNA sequences of SPO11-1 and -2 from all of these plants by RT-PCR. During these experiments we observed that the analyzed plants exhibit a pattern of alternative splicing products of both SPO11 mRNAs. Such an aberrant splicing has previously been described for Arabidopsis and therefore seems to be conserved throughout evolution. Most of the splicing forms of SPO11-1 and -2 seem to be non-functional as they either showed intron retention (IR) or shortened exons. However, the positional distribution and number of alternative splicing events vary strongly between the different plants. The cDNAs showed in most cases premature termination codons (PTCs) due to frameshift. Nevertheless, in some cases we found alternatively spliced but functional cDNAs. These findings let us suggest that alternative splicing of SPO11 depends on the respective gene sequence and on the plant species. Therefore, this conserved mechanism might play a role concerning regulation of SPO11.
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