scholarly journals Premature termination codons in PRPF31 cause retinitis pigmentosa via haploinsufficiency due to nonsense-mediated mRNA decay

2008 ◽  
Vol 118 (4) ◽  
pp. 1519-1531 ◽  
Author(s):  
Thomas Rio Frio ◽  
Nicholas M. Wade ◽  
Adriana Ransijn ◽  
Eliot L. Berson ◽  
Jacques S. Beckmann ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Mrna Decay ◽  
Premature Termination ◽  
Premature Termination Codons ◽  
Nonsense Mediated Mrna Decay

scholarly journals Premature termination codons in SOD1 causing Amyotrophic Lateral Sclerosis are predicted to escape the nonsense-mediated mRNA decay

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Claire Guissart ◽  
Kevin Mouzat ◽  
Jovana Kantar ◽  
Baptiste Louveau ◽  
Paul Vilquin ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mrna Decay ◽  
Premature Termination ◽  
Underlying Mechanism ◽  
Missense Mutations ◽  
Gene Encoding ◽  
Premature Termination Codons ◽  
Nonsense Mediated Mrna Decay ◽  
Inherited Mutations ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is the most common and severe adult-onset motoneuron disease and has currently no effective therapy. Approximately 20% of familial ALS cases are caused by dominantly-inherited mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1), which represents one of the most frequent genetic cause of ALS. Despite the overwhelming majority of ALS-causing missense mutations in SOD1, a minority of premature termination codons (PTCs) have been identified. mRNA harboring PTCs are known to be rapidly degraded by nonsense-mediated mRNA decay (NMD), which limits the production of truncated proteins. The rules of NMD surveillance varying with PTC location in mRNA, we analyzed the localization of PTCs in SOD1 mRNA to evaluate whether or not those PTCs can be triggered to degradation by the NMD pathway. Our study shows that all pathogenic PTCs described in SOD1 so far can theoretically escape the NMD, resulting in the production of truncated protein. This finding supports the hypothesis that haploinsufficiency is not an underlying mechanism of SOD1 mutant-associated ALS and suggests that PTCs found in the regions that trigger NMD are not pathogenic. Such a consideration is particularly important since the availability of SOD1 antisense strategies, in view of variant treatment assignment.

scholarly journals Regulation of Multiple Core Spliceosomal Proteins by Alternative Splicing-Coupled Nonsense-Mediated mRNA Decay

2008 ◽  
Vol 28 (13) ◽  
pp. 4320-4330 ◽  
Author(s):  
Arneet L. Saltzman ◽  
Yoon Ki Kim ◽  
Qun Pan ◽  
Matthew M. Fagnani ◽  
Lynne E. Maquat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Mrna Decay ◽  
Splice Variants ◽  
Cellular Functions ◽  
Regulate Gene Expression ◽  
Premature Termination Codons ◽  
Microarray Profiling ◽  
Nonsense Mediated Mrna Decay ◽  
Regulate Gene

ABSTRACT Alternative splicing (AS) can regulate gene expression by introducing premature termination codons (PTCs) into spliced mRNA that subsequently elicit transcript degradation by the nonsense-mediated mRNA decay (NMD) pathway. However, the range of cellular functions controlled by this process and the factors required are poorly understood. By quantitative AS microarray profiling, we find that there are significant overlaps among the sets of PTC-introducing AS events affected by individual knockdown of the three core human NMD factors, Up-Frameshift 1 (UPF1), UPF2, and UPF3X/B. However, the levels of some PTC-containing splice variants are less or not detectably affected by the knockdown of UPF2 and/or UPF3X, compared with the knockdown of UPF1. The intron sequences flanking the affected alternative exons are often highly conserved, suggesting important regulatory roles for these AS events. The corresponding genes represent diverse cellular functions, and surprisingly, many encode core spliceosomal proteins and assembly factors. We further show that conserved, PTC-introducing AS events are enriched in genes that encode core spliceosomal proteins. Where tested, altering the expression levels of these core spliceosomal components affects the regulation of PTC-containing splice variants from the corresponding genes. Together, our results show that AS-coupled NMD can have different UPF factor requirements and is likely to regulate many general components of the spliceosome. The results further implicate general spliceosomal components in AS regulation.

scholarly journals Nonsense-Mediated mRNA Decay Mutation in Aspergillus nidulans

2006 ◽  
Vol 5 (11) ◽  
pp. 1838-1846 ◽  
Author(s):  
Igor Y. Morozov ◽  
Susana Negrete-Urtasun ◽  
Joan Tilburn ◽  
Christine A. Jansen ◽  
Mark X. Caddick ◽  
...  
Keyword(s):  
Aspergillus Nidulans ◽  
Mrna Decay ◽  
Premature Termination ◽  
Regulation Of Gene Expression ◽  
Premature Termination Codon ◽  
Termination Codon ◽  
Urate Oxidase ◽  
Genes Encoding ◽  
Nonsense Mediated Mrna Decay ◽  
Nonsense Codons

ABSTRACT An Aspergillus nidulans mutation, designated nmdA1, has been selected as a partial suppressor of a frameshift mutation and shown to truncate the homologue of the Saccharomyces cerevisiae nonsense-mediated mRNA decay (NMD) surveillance component Nmd2p/Upf2p. nmdA1 elevates steady-state levels of premature termination codon-containing transcripts, as demonstrated using mutations in genes encoding xanthine dehydrogenase (hxA), urate oxidase (uaZ), the transcription factor mediating regulation of gene expression by ambient pH (pacC), and a protease involved in pH signal transduction (palB). nmdA1 can also stabilize pre-mRNA (unspliced) and wild-type transcripts of certain genes. Certain premature termination codon-containing transcripts which escape NMD are relatively stable, a feature more in common with certain nonsense codon-containing mammalian transcripts than with those in S. cerevisiae. As in S. cerevisiae, 5′ nonsense codons are more effective at triggering NMD than 3′ nonsense codons. Unlike the mammalian situation but in common with S. cerevisiae and other lower eukaryotes, A. nidulans is apparently impervious to the position of premature termination codons with respect to the 3′ exon-exon junction.

scholarly journals VHLFrameshift Mutation as Target of Nonsense-Mediated mRNA Decay inDrosophila melanogasterand Human HEK293 Cell Line

2009 ◽  
Vol 2009 ◽  
pp. 1-9 ◽  
Author(s):  
Lucia Micale ◽  
Lucia Anna Muscarella ◽  
Marco Marzulli ◽  
Bartolomeo Augello ◽  
Patrizia Tritto ◽  
...  
Keyword(s):  
Mrna Decay ◽  
Phenotypic Variability ◽  
Familial Cancer ◽  
Cancer Syndrome ◽  
Hek 293 ◽  
Von Hippel Lindau ◽  
Premature Termination Codons ◽  
Exon 1 ◽  
Nonsense Mediated Mrna Decay ◽  
Human Mutation

There are many well-studied examples of human phenotypes resulting from nonsense or frameshift mutations that are modulated by Nonsense-Mediated mRNA Decay (NMD), a process that typically degrades transcripts containing premature termination codons (PTCs) in order to prevent translation of unnecessary or aberrant transcripts. Different types of germline mutations in theVHLgene cause the von Hippel-Lindau disease, a dominantly inherited familial cancer syndrome with a marked phenotypic variability and age-dependent penetrance. By generating theDrosophilaUAS:Upf1D45Bline we showed the possible involvement of NMD mechanism in the modulation of the c.172delG frameshift mutation located in the exon 1 ofVhlgene. Further, by Quantitative Real-time PCR (QPCR) we demonstrated that the corresponding c.163delG human mutation is targeted by NMD in human HEK 293 cells. The UAS:Upf1D45Bline represents a useful system to identify novel substrates of NMD pathway inDrosophila melanogaster. Finally, we suggest the possible role of NMD on the regulation ofVHLmutations.

scholarly journals Mechanisms and Regulation of Nonsense-Mediated mRNA Decay and Nonsense-Associated Altered Splicing in Lymphoid Cells

2020 ◽  
Author(s):  
Jean-Marie Lambert ◽  
Mohamad Omar Ashi ◽  
Nivine Srour ◽  
Laurent Delpy ◽  
Jérôme Saulière
Keyword(s):  
Quality Control ◽  
Mrna Decay ◽  
Dominant Negative ◽  
Lymphoid Cells ◽  
Surveillance Systems ◽  
Rna Surveillance ◽  
Accelerated Degradation ◽  
Premature Termination Codons ◽  
Rna Quality Control ◽  
Nonsense Mediated Mrna Decay

The presence of premature termination codons (PTCs) in transcripts is dangerous for the cell as they encode potentially deleterious truncated proteins that can act with dominant-negative or gain-of-function effects. To avoid synthesis of these shortened polypeptides, several RNA surveillance systems can be activated to decrease the level of PTC-containing mRNAs. Nonsense-mediated mRNA decay (NMD) ensures an accelerated degradation of mRNAs harboring PTCs by using several key NMD factors such as up-frameshift (UPF) proteins. Another pathway called nonsense-associated altered splicing (NAS) upregulates transcripts that have skipped disturbing PTCs by alternative splicing. Therefore, these RNA quality control processes eliminate abnormal PTC-containing mRNAs from the cells by using positive and negative responses. In this review, we will describe the general mechanisms of NMD and NAS and their respective involvement in the decay of aberrant immunoglobulin and TCR transcripts in lymphoid cells.

scholarly journals Mechanisms and Regulation of Nonsense-Mediated mRNA Decay and Nonsense-Associated Altered Splicing in Lymphocytes

2020 ◽  
Vol 21 (4) ◽  
pp. 1335 ◽  
Author(s):  
Jean-Marie Lambert ◽  
Mohamad Omar Ashi ◽  
Nivine Srour ◽  
Laurent Delpy ◽  
Jérôme Saulière
Keyword(s):  
Quality Control ◽  
Alternative Splicing ◽  
Mrna Decay ◽  
Dominant Negative ◽  
Surveillance Systems ◽  
Rna Surveillance ◽  
Accelerated Degradation ◽  
Premature Termination Codons ◽  
Rna Quality Control ◽  
Nonsense Mediated Mrna Decay

The presence of premature termination codons (PTCs) in transcripts is dangerous for the cell as they encode potentially deleterious truncated proteins that can act with dominant-negative or gain-of-function effects. To avoid the synthesis of these shortened polypeptides, several RNA surveillance systems can be activated to decrease the level of PTC-containing mRNAs. Nonsense-mediated mRNA decay (NMD) ensures an accelerated degradation of mRNAs harboring PTCs by using several key NMD factors such as up-frameshift (UPF) proteins. Another pathway called nonsense-associated altered splicing (NAS) upregulates transcripts that have skipped disturbing PTCs by alternative splicing. Thus, these RNA quality control processes eliminate abnormal PTC-containing mRNAs from the cells by using positive and negative responses. In this review, we describe the general mechanisms of NMD and NAS and their respective involvement in the decay of aberrant immunoglobulin and TCR transcripts in lymphocytes.

Sign in / Sign up

Export Citation Format

Share Document