Splicing in disease: disruption of the splicing code and the decoding machinery

Wang, Guey-Shin; Cooper, Thomas A.

doi:10.1038/nrg2164

Cited by 917 publications

(793 citation statements)

References 116 publications

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“…156 A growing number of reports highlight the role of DNA sequence variation in modulating alternative splicing, which can contribute to disease susceptibility. 157 The MHC class II region has already provided one of the clearest examples of a SNP modulating alternative splicing resulting in common disease through the work of Valentonyte et al (2005) 158 on genetic determinants of sarcoidosis, a chronic granulomatous condition. A genomewide linkage and association analysis resolved variants at butyrophilin-like 2 (a member of the immunoglobulin family) in disease susceptibility and more specifically a G to A nucleotide substitution (rs2076530) within exon 5, which created an alternative splice site, and led to a frameshift and premature stop.…”

Section: Mhc Class II Expression Polymorphism and Disease L Handunnementioning

confidence: 99%

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

et al. 2009

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Major histocompatibility complex (MHC) class II molecules are central to adaptive immune responses and maintenance of selftolerance. Since the early 1970s, the MHC class II region at chromosome 6p21 has been shown to be associated with a remarkable number of autoimmune, inflammatory and infectious diseases. Given that a full explanation for most MHC class II disease associations has not been reached through analysis of structural variation alone, in this review we examine the role of genetic variation in modulating gene expression. We describe the intricate architecture of the MHC class II regulatory system, indicating how its unique characteristics may relate to observed associations with disease. There is evidence that haplotypespecific variation involving proximal promoter sequences can alter the level of gene expression, potentially modifying the emergence and expression of key phenotypic traits. Although much emphasis has been placed on cis-regulatory elements, we also examine the role of more distant enhancer elements together with the evidence of dynamic inter-and intra-chromosomal interactions and epigenetic processes. The role of genetic variation in such mechanisms may hold profound implications for susceptibility to common disease.

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Section: Mhc Class II Expression Polymorphism and Disease L Handunnementioning

confidence: 99%

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

et al. 2009

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“…Using different 5ʹ or 3ʹ splice sites and by including or skipping introns and exons from a single form of pre-mRNA transcript, alternative splicing can generate multiple distinct mRNA isoforms, which increases the proteome size of an organism and is considered a driving force for the biological complexity of metazoans [1,5,6]. Defects in RNA splicing are the causes of numerous human diseases [7,8]. …”

Section: Introductionmentioning

confidence: 99%

RBM-5 modulates U2AF large subunit-dependent alternative splicing inC. elegans

Zhou

Gao

et al. 2018

RNA Biology

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A key step in pre-mRNA splicing is the recognition of 3ʹ splicing sites by the U2AF large and small subunits, a process regulated by numerous trans-acting splicing factors. How these trans-acting factors interact with U2AF in vivo is unclear. From a screen for suppressors of the temperature-sensitive (ts) lethality of the C. elegans U2AF large subunit gene uaf-1(n4588) mutants, we identified mutations in the RNA binding motif gene rbm-5, a homolog of the tumor suppressor gene RBM5. rbm-5 mutations can suppress uaf-1(n4588) ts-lethality by loss of function and neuronal expression of rbm-5 was sufficient to rescue the suppression. Transcriptome analyses indicate that uaf-1(n4588) affected the expression of numerous genes and rbm-5 mutations can partially reverse the abnormal gene expression to levels similar to that of wild type. Though rbm-5 mutations did not obviously affect alternative splicing per se, they can suppress or enhance, in a gene-specific manner, the altered splicing of genes in uaf-1(n4588) mutants. Specifically, the recognition of a weak 3ʹ splice site was more susceptible to the effect of rbm-5. Our findings provide novel in vivo evidence that RBM-5 can modulate UAF-1-dependent RNA splicing and suggest that RBM5 might interact with U2AF large subunit to affect tumor formation.

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“…Recently, many reports have shown that the SNP in UTRs could have an impact on mRNA stability, translation efficiency and gene expression [25][26][27][28]. After searching the microRNA database, no target sequence was found.…”

Section: Discussionmentioning

confidence: 99%