A systematic analysis of disease-associated variants in the 3′ regulatory regions of human protein-coding genes II: the importance of mRNA secondary structure in assessing the functionality of 3′ UTR variants

Chen, Jian‐Min; Férec, Claude; Cooper, David Neil

doi:10.1007/s00439-006-0218-x

Cited by 125 publications

(95 citation statements)

References 246 publications

(184 reference statements)

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“…[52][53][54][55] Similarly, APA has a demonstrated regulatory role in human disease. 30,[56][57][58][59] Thus, coordinated APA and upstream AS could generate alternatively spliced mRNA isoforms with unique 3 0 UTRs that dictate mRNA half-lives and protein product functions (Fig. 1, right arm).…”

Section: Discussionmentioning

confidence: 99%

Coupling between alternative polyadenylation and alternative splicing is limited to terminal introns

et al. 2016

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Alternative polyadenylation has been implicated as an important regulator of gene expression. In some cases, alternative polyadenylation is known to couple with alternative splicing to influence last intron removal. However, it is unknown whether alternative polyadenylation events influence alternative splicing decisions at upstream exons. Knockdown of the polyadenylation factors CFIm25 or CstF64 in HeLa cells was used as an approach in identifying alternative polyadenylation and alternative splicing events on a genome-wide scale. Although hundreds of alternative splicing events were found to be differentially spliced in the knockdown of CstF64, genes associated with alternative polyadenylation did not exhibit an increased incidence of alternative splicing. These results demonstrate that the coupling between alternative polyadenylation and alternative splicing is usually limited to defining the last exon. The striking influence of CstF64 knockdown on alternative splicing can be explained through its effects on UTR selection of known splicing regulators such as hnRNP A2/B1, thereby indirectly influencing splice site selection. We conclude that changes in the expression of the polyadenylation factor CstF64 influences alternative splicing through indirect effects.

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Section: Discussionmentioning

confidence: 99%

Coupling between alternative polyadenylation and alternative splicing is limited to terminal introns

et al. 2016

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“…The secondary structural changes associated with these four variants have been previously predicted by Chen et al (2006b). Although one (DPYSL2), which also had the lowest P-value (0.2289) of the four candidate mutations, was predicted to generate a type 1 secondary structural change with unknown functional significance, the remaining three [as well as the G fi A mutation in the SLITRK1 gene (Abelson et al 2005)] were predicted to generate a pattern I secondary structural change (Chen et al 2006b).…”

Section: Resultsmentioning

confidence: 92%

“…Although one (DPYSL2), which also had the lowest P-value (0.2289) of the four candidate mutations, was predicted to generate a type 1 secondary structural change with unknown functional significance, the remaining three [as well as the G fi A mutation in the SLITRK1 gene (Abelson et al 2005)] were predicted to generate a pattern I secondary structural change (Chen et al 2006b). It is nevertheless impossible to draw any firm conclusions at this stage.…”

Section: Resultsmentioning

confidence: 99%

“…the unreliability of the mfold program (Zuker et al 2003) in cases where input length exceeds a given limit, and the question of whether the predicted secondary structure can be extrapolated to the in vivo situation. In this regard, it is pertinent to note that using 'local' rather than 'global' secondary structure prediction, we identified consistent patterns of secondary structural change that potentiated the discrimination of functional USS variants from their non-functional counterparts (Chen et al 2006b). We should however emphasise that these predictions were made in the context of interactions between mRNAs and their cognate trans-acting proteins.…”

Section: Data Sourcementioning

confidence: 89%

“…Group 5 in Chen et al (2006b)) were excluded owing to their complex nature. Thus, a total of 79 USS variants (viz.…”

Section: Data Sourcementioning

confidence: 99%

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Searching for potential microRNA-binding site mutations amongst known disease-associated 3′ UTR variants

Chuzhanova

Cooper

Férec

et al. 2007

HUGO J

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The 3¢ untranslated regions (3¢ UTRs) of human protein-coding genes play a pivotal role in the regulation of mRNA 3¢ end formation, stability/degradation, nuclear export, subcellular localisation and translation, and hence are particularly rich in cis-acting regulatory elements. One recent addition to the already large repertoire of known cis-acting regulatory elements are the microRNA (miRNA) target sites that are present in the 3¢ UTRs of many human genes.

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Pathological Variations in 3′‐untranslated Regions of Human Genes

Pal¹,

Chatterjee²,

Berwal³

2010

Encyclopedia of Life Sciences

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The 3′‐untranslated regions (UTRs) of messenger ribonucleic acids (mRNAs) play a critical role in the stabilization, localization and translation of mRNAs. Mutations that disrupt functional elements of the 3′‐UTR of mRNAs such as polyadenylation signal, micro RNA (miRNA) target sites and AU‐rich elements lead to production of nonfunctional proteins or reduced amounts of functional proteins. Genetic variations in the 3′‐UTR are associated with disease risk or diseases such as spinocerebellar ataxia 8, Parkinson disease, breast cancer, atopic dermatitis, papillary thyroid carcinoma and many others. With the advent of genetic counselling and promise of personalized medicine, genetic variation in this region of mRNAs is the focus of intense research. Current research shows that this region is of immense significance in the context of translational research. Key concepts: 3′‐Untranslated regions (UTRs) are noncoding regions of mRNAs. The 3′‐UTR is delimited by stop codon (UAA or UAG or UGA) at the 5′ end and poly (A) tail at the 3′ end. Motifs like AU‐rich elements, polyadenylation signal, iron responsive elements and others are involved in mRNA stability, localization and translation. Mutations are changes in the DNA/gene of an organism which are heritable. Mutations in the AU‐rich elements lead to atypical stabilization of mRNA and associated diseases. Mutations that lead to abolition of canonical polyadenylation signal interfere with efficient transcription termination and polyadenylation of mRNA. Mutations in the 3′‐UTR may alter the binding sites of interacting miRNAs or proteins resulting in deregulation of mRNA translation. Single nucleotide polymorphisms (SNPs) in the 3′‐UTR are associated with individual's drug response and disease risk.

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A systematic analysis of disease-associated variants in the 3′ regulatory regions of human protein-coding genes II: the importance of mRNA secondary structure in assessing the functionality of 3′ UTR variants

Cited by 125 publications

References 246 publications

Coupling between alternative polyadenylation and alternative splicing is limited to terminal introns

Coupling between alternative polyadenylation and alternative splicing is limited to terminal introns

Searching for potential microRNA-binding site mutations amongst known disease-associated 3′ UTR variants

Pathological Variations in 3′‐untranslated Regions of Human Genes

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