text: Results 1-25 (1741280)
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  1. Aberrant 3′ splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization Vořechovský, Igor
  2. Global control of aberrant splice-site activation by auxiliary splicing sequences: evidence for a gradient in exon and intron definition Královičová, Jana | Vořechovský, Igor
  3. DBASS3 and DBASS5: databases of aberrant 3′- and 5′-splice sites Buratti, Emanuele | Chivers, Martin | Hwang, Gyulin | Vorechovsky, Igor
  Nucleic Acids Research 2010;39(Database issue):D86-D91.
  DBASS3 and DBASS5 provide comprehensive repositories of new exon boundaries that were induced by pathogenic mutations in human disease genes. Aberrant 5′- and 3′-splice sites were activated either by mutations in the consensus sequences of natural exon–intron junctions (cryptic sites) or elsewhere ('de novo' sites). DBASS3 and DBASS5 currently contain approximately 900 records of cryptic and de novo 3′- and 5′-splice sites that were produced by over a thousand different mutations in approximately 360 genes. DBASS3 and DBASS5 data can be searched by disease phenotype, gene, mutation, location of aberrant splice sites in introns and exons and their distance from authentic counterparts, by bibliographic references and by the splice-site strength estimated with several prediction algorithms. The user can also retrieve reference sequences of both aberrant and authentic splice sites with the underlying mutation. These data will facilitate identification of introns or exons frequently involved in aberrant splicing, mutation analysis of human disease genes and study of germline or somatic mutations that impair RNA processing. Finally, this resource will be useful for fine-tuning splice-site prediction algorithms, better definition of auxiliary splicing signals and design of new reporter assays. DBASS3 and DBASS5 are freely available at http://www.dbass.org.uk/.
  doi:10.1093/nar/gkq887
  PMCID: PMC3013770
  4. Biased exon/intron distribution of cryptic and de novo 3′ splice sites Královičová, Jana | Christensen, Mikkel B. | Vořechovský, Igor
  5. Oriented Scanning Is the Leading Mechanism Underlying 5′ Splice Site Selection in Mammals Borensztajn, Keren | Sobrier, Marie-Laure | Duquesnoy, Philippe | Fischer, Anne-Marie | Tapon-Bretaudière, Jacqueline | Amselem, Serge
  6. Computational analysis of splicing errors and mutations in human transcripts Kurmangaliyev, Yerbol Z | Gelfand, Mikhail S
  7. AU-rich intronic elements affect pre-mRNA 5' splice site selection in Drosophila melanogaster. McCullough, A J | Schuler, M A
  8. Ab initio prediction of mutation-induced cryptic splice-site activation and exon skipping Divina, Petr | Kvitkovicova, Andrea | Buratti, Emanuele | Vorechovsky, Igor
  European Journal of Human Genetics 2009;17(6):759-765.
  doi:10.1038/ejhg.2008.257
  PMCID: PMC2947103
  PMID: 19142208
  mutation; gene; splicing; cryptic splice site; exon skipping; RNA
  9. Genome-Wide Association between Branch Point Properties and Alternative Splicing Corvelo, André | Hallegger, Martina | Smith, Christopher W. J. | Eyras, Eduardo
  10. Comprehensive splicing functional analysis of DNA variants of the BRCA2 gene by hybrid minigenes Acedo, Alberto | Sanz, David J | Durán, Mercedes | Infante, Mar | Pérez-Cabornero, Lucía | Miner, Cristina | Velasco, Eladio A
  Breast Cancer Research : BCR 2012;14(3):R87.
  doi:10.1186/bcr3202
  PMCID: PMC3446350
  PMID: 22632462
  11. Functional Characterization of the spf/ash Splicing Variation in OTC Deficiency of Mice and Man Rivera-Barahona, Ana | Sánchez-Alcudia, Rocío | Viecelli, Hiu Man | Rüfenacht, Veronique | Pérez, Belén | Ugarte, Magdalena | Häberle, Johannes | Thöny, Beat | Desviat, Lourdes Ruiz
  PLoS ONE 2015;10(4):e0122966.
  doi:10.1371/journal.pone.0122966
  PMCID: PMC4390381
  PMID: 25853564
  12. Mutations in the Caenorhabditis elegans U2AF Large Subunit UAF-1 Alter the Choice of a 3′ Splice Site In Vivo Ma, Long | Horvitz, H. Robert
  PLoS Genetics 2009;5(11):e1000708.
  Eukaryotic genes contain intervening intronic sequences that must be removed from pre-mRNA transcripts by RNA splicing to generate functional messenger RNAs. While studying genes that encode and control a presumptive muscle potassium channel complex in the nematode Caenorhabditis elegans, we found that mutations in two splicing factors, the U2AF large subunit and SF1/BBP suppress the rubberband Unc phenotype caused by a rare missense mutation in the gene unc-93. Mutations affecting the U2AF large subunit caused the recognition of a cryptic 3′ splice site generated by the unc-93 mutation, providing in vivo evidence that the U2AF large subunit can affect splice-site selection. By contrast, an SF1/BBP mutation that suppressed the rubberband Unc phenotype did not cause splicing using this cryptic 3′ splice site. Our genetic studies identified a region of the U2AF large subunit important for its effect on 3′ splice-site choice. Our mutagenesis analysis of in vivo transgene splicing identified a positional effect on weak 3′ splice site selection and nucleotides of the endogenous 3′ splice site important for recognition. The system we have defined should facilitate future in vivo analyses of pre–mRNA splicing.
  doi:10.1371/journal.pgen.1000708
  PMCID: PMC2762039
  PMID: 19893607
  13. Genomic features defining exonic variants that modulate splicing Woolfe, Adam | Mullikin, James C | Elnitski, Laura
  Genome Biology 2010;11(2):R20.
  A comparative analysis of SNPs and their exonic and intronic environments identifies the features predictive of splice affecting variants. Background
  Single point mutations at both synonymous and non-synonymous positions within exons can have severe effects on gene function through disruption of splicing. Predicting these mutations in silico purely from the genomic sequence is difficult due to an incomplete understanding of the multiple factors that may be responsible. In addition, little is known about which computational prediction approaches, such as those involving exonic splicing enhancers and exonic splicing silencers, are most informative.
  We assessed the features of single-nucleotide genomic variants verified to cause exon skipping and compared them to a large set of coding SNPs common in the human population, which are likely to have no effect on splicing. Our findings implicate a number of features important for their ability to discriminate splice-affecting variants, including the naturally occurring density of exonic splicing enhancers and exonic splicing silencers of the exon and intronic environment, extensive changes in the number of predicted exonic splicing enhancers and exonic splicing silencers, proximity to the splice junctions and evolutionary constraint of the region surrounding the variant. By extending this approach to additional datasets, we also identified relevant features of variants that cause increased exon inclusion and ectopic splice site activation.
  We identified a number of features that have statistically significant representation among exonic variants that modulate splicing. These analyses highlight putative mechanisms responsible for splicing outcome and emphasize the role of features important for exon definition. We developed a web-tool, Skippy, to score coding variants for these relevant splice-modulating features.
  doi:10.1186/gb-2010-11-2-r20
  PMCID: PMC2872880
  PMID: 20158892
  14. Whole Exome Sequencing Reveals Novel PHEX Splice Site Mutations in Patients with Hypophosphatemic Rickets Ma, Sara L. | Vega-Warner, Virginia | Gillies, Christopher | Sampson, Matthew G. | Kher, Vijay | Sethi, Sidharth K. | Otto, Edgar A.
  15. A class of human exons with predicted distant branch points revealed by analysis of AG dinucleotide exclusion zones Gooding, Clare | Clark, Francis | Wollerton, Matthew C | Grellscheid, Sushma-Nagaraja | Groom, Harriet | Smith, Christopher WJ
  Genome Biology 2006;7(1):R1.
  Exons with predicted branch points were identified from a large dataset of human exons and the importance of these branch points for splicing was verified.
  doi:10.1186/gb-2006-7-1-r1
  PMCID: PMC1431707
  PMID: 16507133
  16. Large introns in relation to alternative splicing and gene evolution: a case study of Drosophila bruno-3 Kandul, Nikolai P | Noor, Mohamed AF
  17. Factors affecting authentic 5' splice site selection in plant nuclei. McCullough, A J | Lou, H | Schuler, M A
  Molecular and Cellular Biology 1993;13(3):1323-1331.
  PMCID: PMC359441
  PMID: 8441378
  18. Normal and abnormal mechanisms of gene splicing and relevance to inherited skin diseases Wessagowit, Vesarat | Nalla, Vijay K. | Rogan, Peter K. | McGrath, John A.
  Journal of dermatological science 2005;40(2):73-84.
  The process of excising introns from pre-mRNA complexes is directed by specific genomic DNA sequences at intron—exon borders known as splice sites. These regions contain well-conserved motifs which allow the splicing process to proceed in a regulated and structured manner. However, as well as conventional splicing, several genes have the inherent capacity to undergo alternative splicing, thus allowing synthesis of multiple gene transcripts, perhaps with different functional properties. Within the human genome, therefore, through alternative splicing, it is possible to generate over 100,000 physiological gene products from the 35,000 or so known genes. Abnormalities in normal or alternative splicing, however, account for about 15% of all inherited single gene disorders, including many with a skin phenotype. These splicing abnormalities may arise through inherited mutations in constitutive splice sites or other critical intronic or exonic regions. This review article examines the process of normal intron—exon splicing, as well as what is known about alternative splicing of human genes. The review then addresses pathological disruption of normal intron—exon splicing that leads to inherited skin diseases, either resulting from mutations in sequences that have a direct influence on splicing or that generate cryptic splice sites. Examples of aberrant splicing, especially for the COL7A1 gene in patients with dystrophic epidermolysis bullosa, are discussed and illustrated. The review also examines a number of recently introduced computational tools that can be used to predict whether genomic DNA sequences changes may affect splice site selection and how robust the influence of such mutations might be on splicing.
  doi:10.1016/j.jdermsci.2005.05.006
  PMCID: PMC1351063
  PMID: 16054339
  Inherited skin disease; RNA; Intron; Exon; Gene mutation; Splice site; Cryptic splicing
  19. Alu Exonization Events Reveal Features Required for Precise Recognition of Exons by the Splicing Machinery Schwartz, Schraga | Gal-Mark, Nurit | Kfir, Nir | Oren, Ram | Kim, Eddo | Ast, Gil
  20. The Emergence of Alternative 3′ and 5′ Splice Site Exons from Constitutive Exons Koren, Eli | Lev-Maor, Galit | Ast, Gil
  21. BAP1 Missense Mutation c.2054 A>T (p.E685V) Completely Disrupts Normal Splicing through Creation of a Novel 5' Splice Site in a Human Mesothelioma Cell Line Morrison, Arianne | Chekaluk, Yvonne | Bacares, Ruben | Ladanyi, Marc | Zhang, Liying
  PLoS ONE 2015;10(4):e0119224.
  BAP1 is a tumor suppressor gene that is lost or deleted in diverse cancers, including uveal mela¬noma, malignant pleural mesothelioma (MPM), clear cell renal carcinoma, and cholangiocarcinoma. Recently, BAP1 germline mutations have been reported in families with combinations of these same cancers. A particular challenge for mutation screening is the classification of non-truncating BAP1 sequence variants because it is not known whether these subtle changes can affect the protein function sufficiently to predispose to cancer development. Here we report mRNA splicing analysis on a homozygous substitution mutation, BAP1 c. 2054 A&T (p.Glu685Val), identified in an MPM cell line derived from a mesothelioma patient. The mutation occurred at the 3rd nucleotide from the 3' end of exon 16. RT-PCR, cloning and subsequent sequencing revealed several aberrant splicing products not observed in the controls: 1) a 4 bp deletion at the end of exon 16 in all clones derived from the major splicing product. The BAP1 c. 2054 A&T mutation introduced a new 5' splice site (GU), which resulted in the deletion of 4 base pairs and presumably protein truncation; 2) a variety of alternative splicing products that led to retention of different introns: introns 14–16; introns 15–16; intron 14 and intron 16; 3) partial intron 14 and 15 retentions caused by activation of alternative 3' splice acceptor sites (AG) in the introns. Taken together, we were unable to detect any correctly spliced mRNA transcripts in this cell line. These results suggest that aberrant splicing caused by this mutation is quite efficient as it completely abolishes normal splicing through creation of a novel 5' splice site and activation of cryptic splice sites. These data support the conclusion that BAP1 c.2054 A&T (p.E685V) variant is a pathogenic mutation and contributes to MPM through disruption of normal splicing.
  doi:10.1371/journal.pone.0119224
  PMCID: PMC4382119
  PMID: 25830670
  22. Re-splicing of mature mRNA in cancer cells promotes activation of distant weak alternative splice sites Kameyama, Toshiki | Suzuki, Hitoshi | Mayeda, Akila
  23. A naturally arising mutation of a potential silencer of exon splicing in human immunodeficiency virus type 1 induces dominant aberrant splicing and arrests virus production. Wentz, M P | Moore, B E | Cloyd, M W | Berget, S M | Donehower, L A
  Journal of Virology 1997;71(11):8542-8551.
  We have isolated a naturally arising human immunodeficiency type 1 (HIV-1) mutant containing a point mutation within the env gene. The point mutation resulted in complete loss of balanced splicing, with dominant production of aberrant mRNAs. The aberrant RNAs arose via activation of normally cryptic splice sites flanking the mutation within the env terminal exon to create exon 6D, which was subsequently incorporated in aberrant env, tat, rev, and nef mRNAs. Aberrant multiply spliced messages contributed to reduced virus replication as a result of a reduction in wild-type Rev protein. The point mutation within exon 6D activated exon 6D inclusion when the exon and its flanking splice sites were transferred to a heterologous minigene. Introduction of the point mutation into an otherwise wild-type HIV-1 proviral clone resulted in virus that was severely inhibited for replication in T cells and displayed elevated usage of exon 6D. Exon 6D contains a bipartite element similar to that seen in tat exon 3 of HIV-1, consisting of a potential exon splicing silencer (ESS) juxtaposed to a purine-rich sequence similar to known exon splicing enhancers. In the absence of a flanking 5' splice site, the point mutation within the exon 6D ESS-like element strongly activated env splicing, suggesting that the putative ESS plays a natural role in limiting the level of env splicing. We propose, therefore, that exon silencers may be a common element in the HIV-1 genome used to create balanced splicing of multiple products from a single precursor RNA.
  PMCID: PMC192318
  PMID: 9343212
  24. Alternative splicing of beta-tropomyosin pre-mRNA: multiple cis-elements can contribute to the use of the 5'- and 3'-splice sites of the nonmuscle/smooth muscle exon 6. Tsukahara, T | Casciato, C | Helfman, D M
  25. Functional studies on the ATM intronic splicing processing element Lewandowska, Marzena A. | Stuani, Cristiana | Parvizpur, Alireza | Baralle, Francisco E. | Pagani, Franco
  Nucleic Acids Research 2005;33(13):4007-4015.
  In disease-associated genes, the understanding of the functional significance of deep intronic nucleotide variants may represent a difficult challenge. We have previously reported a new disease-causing mechanism that involves an intronic splicing processing element (ISPE) in ATM, composed of adjacent consensus 5′ and 3′ splice sites. A GTAA deletion within ISPE maintains potential adjacent splice sites, disrupts a non-canonical U1 snRNP interaction and activates an aberrant exon. In this paper, we demonstrate that binding of U1 snRNA through complementarity within a ∼40 nt window downstream of the ISPE prevents aberrant splicing. By selective mutagenesis at the adjacent consensus ISPE splice sites, we show that this effect is not due to a resplicing process occurring at the ISPE. Functional comparison of the ATM mouse counterpart and evaluation of the pre-mRNA splicing intermediates derived from affected cell lines and hybrid minigene assays indicate that U1 snRNP binding at the ISPE interferes with the cryptic acceptor site. Activation of this site results in a stringent 5′–3′ order of intron sequence removal around the cryptic exon. Artificial U1 snRNA loading by complementarity to heterologous exonic sequences represents a potential therapeutic method to prevent the usage of an aberrant CFTR cryptic exon. Our results suggest that ISPE-like intronic elements binding U1 snRNPs may regulate correct intron processing.