Dataset Information


Genome-wide consequences of compromised NMD and their relavence for variable clinical phenotype of patients with UPF3B mutations [RNA-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens  

SUBMITTER: A M Addington   Jozef Gecz  Wai-kin Chan  Frederic Laumonnier  Jayson Rodriguez  Lam S Nguyen  Lulu Huang  Lachlan Jolly  Cheryl Shoubridge  Miles F Wilkinson  Martine Raynaud  Anand Srivastava  Mark Corbett 

PROVIDER: E-GEOD-27199 | ArrayExpress | 2011-11-01



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Transcriptome profiling of UPF3B/NMD-deficient lymphoblastoid cells from patients with various forms of intellectual disability.

Nguyen L S LS   Jolly L L   Shoubridge C C   Chan W K WK   Huang L L   Laumonnier F F   Raynaud M M   Hackett A A   Field M M   Rodriguez J J   Srivastava A K AK   Lee Y Y   Long R R   Addington A M AM   Rapoport J L JL   Suren S S   Hahn C N CN   Gamble J J   Wilkinson M F MF   Corbett M A MA   Gecz J J  

Molecular psychiatry 20111220 11

The nonsense-mediated mRNA decay (NMD) pathway was originally discovered by virtue of its ability to rapidly degrade aberrant mRNAs with premature termination codons. More recently, it was shown that NMD also directly regulates subsets of normal transcripts, suggesting that NMD has roles in normal biological processes. Indeed, several NMD factors have been shown to regulate neurological events (for example, neurogenesis and synaptic plasticity) in numerous vertebrate species. In man, mutations i  ...[more]

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