Dosage imbalance of NMD genes is associated with intellectual disability
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE35420 | GEO | 2012/12/31
SECONDARY ACCESSION(S): PRJNA152581
REPOSITORIES: GEO
Similar Datasets
Project description:Nonsense-mediated mRNA decay (NMD) functions to degrade transcripts bearing premature stop codon (PTC) and is a crucial regulator of gene expression. NMD and the UPF3B gene have been implicated as the cause of various forms of intellectual disability (ID) and other neurological symptoms. Here, we reports three patients with global developmental delay carrying hemizygous deletions of the UPF2 gene, another important member of the NMD pathway and direct interacting partner of UPF3B. Using RNA-SEQ on lymphoblastoid cells from UPF2 deletion patients, we identified 1009 differently expressed genes (DEGs). 38% of these DEGs overlapped with DEGs identified in UPF3B patients. More importantly, 95% of all DEGs in either UPF2 or UPF3B patients share the same trend of de-regulation. This demonstrates that the transcriptome deregulation in these two patient groups is similar and that UPF2 should be considered as a new candidate gene for ID in man. We expanded our inq`uiries and performed a comprehensive search for copy number variations (CNVs) encompassing all NMD genes in cohorts of ID patients and controls. We found that UPF2, UPF3A, Y14, SMG6 and EIF4A3 are frequently deleted and/or duplicated in ID patients. These CNVs are likely to be the root of the problems or to act as predisposing factors. Our results suggest that dosage imbalance of NMD factors is associated with ID and further emphasize the importance of NMD in normal learning and memory processes.
2012-12-31 | E-GEOD-35420 | biostudies-arrayexpress
Project description:The paralogous proteins UPF3A and UPF3B are involved in recognizing defective mRNAs that are degraded by nonsense-mediated mRNA decay (NMD). While UPF3B has been demonstrated to support NMD, UPF3A was reported to act either an NMD activator or an NMD inhibitor. Here, we present a comprehensive functional analysis of UPF3A and UPF3B in human cells using overexpression, knockdowns, knockouts (KO) and rescue experiments. Overexpression or knockout of UPF3A did not result in detectable changes in global NMD activity or other specific transcriptome alterations . NMD activity was also virtually unchanged in UPF3B KO cells. In contrast, the co-depletion or co-knockout of UPF3A and UPF3B resulted in a marked NMD inhibition and a global upregulation of PTC-containing transcripts. In rescue experiments UPF3B was fully functional when either UPF2- or EJC binding was impaired . However, the deletion of both interaction sites or one interaction site and a central region of UPF3B impaired its NMD function. Altogether, our work identifies critical functional domains of UPF3B and establishes redundant roles of UPF3A and UPF3B during NMD.
2022-05-04 | PXD027120 | Pride
Project description:Nonsense-mediated mRNA decay (NMD) surveillance pathways are best known to be involved in the degradation of mRNA with premature termination codons (PTCs). More recent studies demonstrate that the role of NMD pathways goes well beyond the degradation of PTC containing mRNA, into the regulation of cell function and thus normal development. We have taken advantage of the availability of naturally occurring loss of function mutations in the UPF3B gene, a major component of the exon junction complex (EJC), to inquire about genome-wide consequences of compromised NMD. We identify that about 5% of the lymphoblastoid cell transcriptome is directly or indirectly impacted upon in patients with UPF3B mutations with minimal effect on alternative splicing. We identify UPF3A-NMD as a likely, major modifier of the UPF3B patient phenotype through variable UPF3A protein stabilisation. Among the most consistently deregulated direct targets of UPF3B-NMD we identify the ARHGAP24 as the most likely gene implicated in the neuronal phenotype of UPF3B patients.
2011-11-01 | GSE27412 | GEO
Project description:Nonsense-mediated mRNA decay (NMD) surveillance pathways are best known to be involved in the degradation of mRNA with premature termination codons (PTCs). More recent studies demonstrate that the role of NMD pathways goes well beyond the degradation of PTC containing mRNA, into the regulation of cell function and thus normal development. We have taken advantage of the availability of naturally occurring loss of function mutations in the UPF3B gene, a major component of the exon junction complex (EJC), to inquire about genome-wide consequences of compromised NMD. We identify that about 5% of the lymphoblastoid cell transcriptome is directly or indirectly impacted upon in patients with UPF3B mutations with minimal effect on alternative splicing. We identify UPF3A-NMD as a likely, major modifier of the UPF3B patient phenotype through variable UPF3A protein stabilisation. Among the most consistently deregulated direct targets of UPF3B-NMD we identify the ARHGAP24 as the most likely gene implicated in the neuronal phenotype of UPF3B patients.
2011-11-01 | GSE27199 | GEO
Project description:Nonsense-mediated mRNA decay (NMD) surveillance pathways are best known to be involved in the degradation of mRNA with premature termination codons (PTCs). More recent studies demonstrate that the role of NMD pathways goes well beyond the degradation of PTC containing mRNA, into the regulation of cell function and thus normal development. We have taken advantage of the availability of naturally occurring loss of function mutations in the UPF3B gene, a major component of the exon junction complex (EJC), to inquire about genome-wide consequences of compromised NMD. We identify that about 5% of the lymphoblastoid cell transcriptome is directly or indirectly impacted upon in patients with UPF3B mutations with minimal effect on alternative splicing. We identify UPF3A-NMD as a likely, major modifier of the UPF3B patient phenotype through variable UPF3A protein stabilisation. Among the most consistently deregulated direct targets of UPF3B-NMD we identify the ARHGAP24 as the most likely gene implicated in the neuronal phenotype of UPF3B patients.
2011-11-01 | GSE27125 | GEO
Project description:Nonsense-mediated mRNA decay (NMD) surveillance pathways are best known to be involved in the degradation of mRNA with premature termination codons (PTCs). More recent studies demonstrate that the role of NMD pathways goes well beyond the degradation of PTC containing mRNA, into the regulation of cell function and thus normal development. We have taken advantage of the availability of naturally occurring loss of function mutations in the UPF3B gene, a major component of the exon junction complex (EJC), to inquire about genome-wide consequences of compromised NMD. We identify that about 5% of the lymphoblastoid cell transcriptome is directly or indirectly impacted upon in patients with UPF3B mutations with minimal effect on alternative splicing. We identify UPF3A-NMD as a likely, major modifier of the UPF3B patient phenotype through variable UPF3A protein stabilisation. Among the most consistently deregulated direct targets of UPF3B-NMD we identify the ARHGAP24 as the most likely gene implicated in the neuronal phenotype of UPF3B patients. To assess the impact of UPF3B-NMD deficiency on human transcriptome, we sequenced polyA RNA extracted from lymphoblastoid cell lines of patients (n=4) and controls (n=2). We complemented the analysis using Affymetrix Human Exon 1.0 St array using total RNA of the same cell line from patients (n=5, 3 of whom were also sequenced) and controls (n=5). Moreover, we overlapped identified differently expressed genes with copy number variation data of the patients, obtained using Illumina Human Omniexpress chip, to exclude possible false positive.
2011-11-01 | E-GEOD-27412 | biostudies-arrayexpress
Project description:Nonsense-mediated mRNA decay (NMD) surveillance pathways are best known to be involved in the degradation of mRNA with premature termination codons (PTCs). More recent studies demonstrate that the role of NMD pathways goes well beyond the degradation of PTC containing mRNA, into the regulation of cell function and thus normal development. We have taken advantage of the availability of naturally occurring loss of function mutations in the UPF3B gene, a major component of the exon junction complex (EJC), to inquire about genome-wide consequences of compromised NMD. We identify that about 5% of the lymphoblastoid cell transcriptome is directly or indirectly impacted upon in patients with UPF3B mutations with minimal effect on alternative splicing. We identify UPF3A-NMD as a likely, major modifier of the UPF3B patient phenotype through variable UPF3A protein stabilisation. Among the most consistently deregulated direct targets of UPF3B-NMD we identify the ARHGAP24 as the most likely gene implicated in the neuronal phenotype of UPF3B patients. To assess the impact of UPF3B-NMD deficiency on human transcriptome, we sequenced polyA RNA extracted from lymphoblastoid cell lines of patients (n=4) and controls (n=2). We complemented the analysis using Affymetrix Human Exon 1.0 St array using total RNA of the same cell line from patients (n=5, 3 of whom were also sequenced) and controls (n=5). Moreover, we overlapped identified differently expressed genes with copy number variation data of the patients, obtained using Illumina Human Omniexpress chip, to exclude possible false positive.
2011-11-01 | E-GEOD-27125 | biostudies-arrayexpress
Project description:Nonsense-mediated mRNA decay (NMD) surveillance pathways are best known to be involved in the degradation of mRNA with premature termination codons (PTCs). More recent studies demonstrate that the role of NMD pathways goes well beyond the degradation of PTC containing mRNA, into the regulation of cell function and thus normal development. We have taken advantage of the availability of naturally occurring loss of function mutations in the UPF3B gene, a major component of the exon junction complex (EJC), to inquire about genome-wide consequences of compromised NMD. We identify that about 5% of the lymphoblastoid cell transcriptome is directly or indirectly impacted upon in patients with UPF3B mutations with minimal effect on alternative splicing. We identify UPF3A-NMD as a likely, major modifier of the UPF3B patient phenotype through variable UPF3A protein stabilisation. Among the most consistently deregulated direct targets of UPF3B-NMD we identify the ARHGAP24 as the most likely gene implicated in the neuronal phenotype of UPF3B patients. To assess the impact of UPF3B-NMD deficiency on human transcriptome, we sequenced polyA RNA extracted from lymphoblastoid cell lines of patients (n=4) and controls (n=2). We complemented the analysis using Affymetrix Human Exon 1.0 St array using total RNA of the same cell line from patients (n=5, 3 of whom were also sequenced) and controls (n=5). Moreover, we overlapped identified differently expressed genes with copy number variation data of the patients, obtained using Illumina Human Omniexpress chip, to exclude possible false positive. Supplementary file: A splice junction reference file generated for alignment of junction reads. Alignment files linked to individual Sample records.
2011-11-01 | E-GEOD-27199 | biostudies-arrayexpress
Project description:All eukaryotes studied to date have the capacity to detect and degrade mRNAs harboring premature translation termination codons (PTCs) in a process called nonsense-mediated mRNA decay (NMD) (reviewed in Wagner E & Lykke-Andersen J, 2002). This surveillance system allows the cell to prevent the expression of potentially harmful truncated proteins. trans-acting factors required for NMD in Drosophila are the proteins UPF1, UPF2, UPF3, SMG-1, SMG-5 and SMG-6. To identify mRNAs naturally regulated by NMD, we analyzed expression profiles in Drosophila cells RNAi-depleted of known NMD factors using high-density oligonucleotide arrays.
2005-11-01 | E-MEXP-202 | biostudies-arrayexpress
Project description:A major task in analyzing alternative splicing (AS) by RNA-Seq is to explore and quantify the differential representation of various splice classes and the protein-coding potential of the mapped reads. To this end, we have generated a streamlined bioinformatic pipeline available to the scientific community, which maps RNA-Seq reads to a complex combinatorial database of exon-exon junctions for the unique junction discovery, PTC detection and identification of splice isoforms. Hence, we have incorporated a splice isoform inference and PTC detection algorithm, which facilitates a highly accurate mapping and prediction of splice isoform junctions and nonsense-mediated mRNA decay (NMD)-susceptibility. We used this pipeline to investigate the complexity of the transcriptome and global role of AS-NMD in vivo in mammalian cells, by taking advantage of our Upf2 conditional knock-out mouse. Using tissue-specific Cre deleter strains, we have previously demonstrated in vivo that NMD acts to degrade many transcripts that results from AS. Also, ablating UPF2 (a core NMD factor) in the mouse leads to rapid mortality and collapse of most organs tested (Thoren et al., 2010; Weischenfeldt et al., 2008), suggesting an essential function for NMD in AS. To explore the effect of NMD on global splicing and to generate and validate an attractive bioinformatic pipeline for the scientific community to study AS and NMD, we chose to analyze two different mammalian organ systems with distinct phenotypes upon UPF2 ablation to test the robustness and dynamic range of the analysis. In one end of the spectrum, we chose to analyze the liver, wherein removal of UPF2 results in failure in liver metabolism and a high mortality rate (Thoren et al., 2010). To profile a less affected tissue, we chose to analyze bone marrow-derived macrophages (BMMs). These are macrophages that differentiate in vitro and Upf2 deleted BMMs are completely devoid of NMD activity but nevertheless show no morphological or functional phenotype compared to wild-type controls (Weischenfeldt et al., 2008). Thus, we were able to make a direct comparison between these two tissues to demonstrate the potency of our Isoform and PTC detection pipeline described below, which will allow the scientific community to analyze transcriptome data for global AS and NMD-susceptibility. Examination of UPF2 WT vs. KO in two different murine tissues (liver, bone marrow-derived macrophages).
2012-05-01 | E-GEOD-26561 | biostudies-arrayexpress