Evidence in disease and non-disease contexts that nonsense mutations cause altered splicing via motif disruption.

Nucleic Acids Research
Liam AbrahamsLaurence D Hurst


Transcripts containing premature termination codons (PTCs) can be subject to nonsense-associated alternative splicing (NAS). Two models have been evoked to explain this, scanning and splice motif disruption. The latter postulates that exonic cis motifs, such as exonic splice enhancers (ESEs), are disrupted by nonsense mutations. We employ genome-wide transcriptomic and k-mer enrichment methods to scrutinize this model. First, we show that ESEs are prone to disruptive nonsense mutations owing to their purine richness and paucity of TGA, TAA and TAG. The motif model correctly predicts that NAS rates should be low (we estimate 5-30%) and approximately in line with estimates for the rate at which random point mutations disrupt splicing (8-20%). Further, we find that, as expected, NAS-associated PTCs are predictable from nucleotide-based machine learning approaches to predict splice disruption and, at least for pathogenic variants, are enriched in ESEs. Finally, we find that both in and out of frame mutations to TAA, TGA or TAG are associated with exon skipping. While a higher relative frequency of such skip-inducing mutations in-frame than out of frame lends some credence to the scanning model, these results reinforce the importanc...Continue Reading


Nov 7, 1998·Mutation Research·C R Valentine
Feb 20, 1999·Cell·M W Hentze, A E Kulozik
May 26, 1999·Proceedings of the National Academy of Sciences of the United States of America·C L LorsonB Wirth
May 18, 2001·Nature·J Taipale, P A Beachy
Feb 12, 2002·The Journal of Clinical Endocrinology and Metabolism·Chanda T MoseleyJohn A Phillips
Feb 16, 2002·Methods : a Companion to Methods in Enzymology·K J Livak, T D Schmittgen
Feb 19, 2002·EMBO Reports·Jun WangMiles F Wilkinson
Apr 23, 2002·Nature Reviews. Genetics·Luca CartegniAdrian R Krainer
Jun 4, 2002·Nature Cell Biology·Miles F Wilkinson, Ann-Bin Shyu
Jul 13, 2002·Science·William G FairbrotherChristopher B Burge
Jul 30, 2002·American Journal of Human Genetics·James D FackenthalOlufunmilayo I Olopade
Jul 25, 2003·American Journal of Human Genetics·Nan YangKathryn North
Aug 16, 2003·Science·David A BuchnerMiriam H Meisler
Jul 31, 2004·Nature Genetics·Jill A HolbrookAndreas E Kulozik
Aug 3, 2004·Journal of Computational Biology : a Journal of Computational Molecular Cell Biology·Gene Yeo, Christopher B Burge
Sep 2, 2004·PLoS Biology·William G FairbrotherPhillip A Sharp
Dec 21, 2004·Cell·Zefeng WangChristopher B Burge
Mar 22, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Nicole PfarrJoachim Pohlenz
Apr 15, 2005·Nature·Tannishtha Reya, Hans Clevers
Apr 30, 2005·Journal of Cell Science·Lynne E Maquat
Jun 24, 2005·Human Molecular Genetics·Natalay KouprinaVladimir Larionov
Jul 20, 2005·Proceedings of the National Academy of Sciences of the United States of America·Thomas R HawnAlan Aderem
Oct 14, 2005·Molecular Biology and Evolution·Joanna L ParmleyLaurence D Hurst
Dec 2, 2005·Journal of Molecular Evolution·David B Carlini, Jordan E Genut
Feb 15, 2007·PLoS Biology·Joanna L ParmleyLaurence D Hurst

❮ Previous
Next ❯

Related Concepts

Related Feeds

Blood Clotting Disorders

Thrombophilia includes conditions with increased tendency for excessive blood clotting. Blood clotting occurs when the body has insufficient amounts of specialized proteins that make blood clot and stop bleeding. Here is the latest research on blood clotting disorders.

Alternative splicing

Alternative splicing a regulated gene expression process that allows a single genetic sequence to code for multiple proteins. Here is that latest research.