Nucleic Acids Research, 2003, Vol. 31, No. 13 3568-3571
© 2003 Oxford University Press
ESEfinder: a web resource to identify exonic splicing enhancers
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
*To whom correspondence should be addressed. Tel: +1 516 3678417; Fax: +1 516 3678453; Email: krainer{at}cshl.edu
Received February 14, 2003; Revised and Accepted April 7, 2003
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONDESCRIPTIONDISCUSSIONREFERENCES |
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Point mutations frequently cause genetic diseases by disrupting the correct pattern of pre-mRNA splicing. The effect of a point mutation within a coding sequence is traditionally attributed to the deduced change in the corresponding amino acid. However, some point mutations can have much more severe effects on the structure of the encoded protein, for example when they inactivate an exonic splicing enhancer (ESE), thereby resulting in exon skipping. ESEs also appear to be especially important in exons that normally undergo alternative splicing. Different classes of ESE consensus motifs have been described, but they are not always easily identified. ESEfinder (http://exon.cshl.edu/ESE/) is a web-based resource that facilitates rapid analysis of exon sequences to identify putative ESEs responsive to the human SR proteins SF2/ASF, SC35, SRp40 and SRp55, and to predict whether exonic mutations disrupt such elements.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONDESCRIPTIONDISCUSSIONREFERENCES |
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Accurate and efficient removal of introns from pre-mRNAs is essential to ensure correct gene expression. However, the information content present in the canonical splice signals (5' splice site, branch site and 3' splice site) is insufficient to precisely define exons, as a large excess of sequences that conform to these weakly defined consensus elements is present in introns but these sequences are never used (1,2). Additional regulatory cis-elements exist in the form of splicing enhancers and silencers (3). These elements become particularly important in the presence of weak splice sites or when alternative splicing is involved. It is estimated that over 60% of human genes undergo alternative splicing (4). Not only is this one of the main mechanisms by which the relatively small number of human genes accounts for the complexity of the proteome, but the generation of different isoforms can be differentially regulated depending on developmental stage, cell type and in response to a wide array of physiological and pathological signals (4,5).
Up to 50% of all point mutations responsible for genetic diseases cause aberrant splicing (3). Such mutations can disrupt splicing by directly inactivating or creating a splice site, by activating a cryptic splice site or by interfering with splicing regulatory elements. Point mutations in the coding regions of genes were traditionally assumed to exert their effects by altering single amino acids in the encoded proteins. However, some of these exonic mutations also affect pre-mRNA splicing. Nonsense, missense and even translationally silent mutations can disrupt exonic splicing enhancers (ESEs) and cause the splicing machinery to skip the mutant exon, with dramatic effects on the structure of the gene product. Since in most cases the effects of mutations are predicted solely based on genomic sequence information, the prevalence of mutations whose primary consequence is aberrant splicing has been substantially underestimated (3).
ESEs are common in both alternative and constitutive exons, where they act as binding sites for Ser/Arg-rich proteins (SR proteins), a family of conserved splicing factors that participate in multiple steps of the splicing pathway (6). SR proteins bind to ESEs through their RNA-binding domain, and promote exon definition by recruiting spliceosomal components via protein–protein interactions mediated by their RS domain and/or by antagonizing the action of nearby splicing silencers. Different SR proteins have different substrate specificities, and multiple classes of ESE consensus motifs have been described (3,6,7).
We previously used functional SELEX [Systematic Evolution of Ligands by Exponential enrichment (8)], to identify ESE motifs specific for a subset of SR proteins (9,10). In this approach, a natural enhancer in an IgM minigene was replaced by random 20 nt sequences from an oligonucleotide library. The resulting pool of minigenes was then used to generate pre-mRNA transcripts, which were spliced as a pool in vitro under conditions in which splicing was completely dependent on both an ESE and a recombinant SR protein able to productively recognize this ESE. Spliced mRNAs were gel-purified, amplified and used to rebuild minigene templates, allowing the procedure to be iterated. Specific ESE motifs were thus gradually enriched and eventually cloned, sequenced and individually tested. Using the sequences that resulted from the functional selection procedure, we derived nucleotide-frequency matrices (available on the web site), which define consensus motifs for these SR proteins. The motifs are short (6–8 nt), degenerate and can partially overlap (3) (Fig. 1). Here we describe the implementation of the motif-scoring matrices in a web-based program called ESEfinder (release 2.0: http://exon.cshl.edu/ESE/) which allows scanning of nucleotide sequences to predict putative ESEs responsive to the human SR proteins SF2/ASF, SC35, SRp40 or SRp55. ESEfinder has been freely available for non commercial uses since May 2002, and it has already been used successfully to predict ESEs and/or their disruption in a variety of genes, including ACF (11), BRCA1 (12), BRCA2 (13), FBN1 (14), IGF1 (15), PDHA1 (16), SMN1 (17), SMN2 (17), TNFRSF5 (18), CFTR (19,20) and others.
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DESCRIPTION |
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TOPABSTRACTINTRODUCTIONDESCRIPTIONDISCUSSIONREFERENCES |
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ESEfinder performs searches for putative ESEs in query sequences by using weight matrices corresponding to the motifs for four different human SR proteins. The matrices are based on frequency values derived from the alignment of winner sequences obtained by functional SELEX experiments, adjusted on the basis of the background nucleotide frequency of the initial SELEX library, which was made by chemical synthesis (9,10). We have now developed a user-friendly WWW interface and a representation of the program output is shown in Figure 2.
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The query sequences can be directly pasted into the input box or can be uploaded from a text file. Multiple sequences can be analyzed simultaneously, provided that a FASTA-format descriptive line (beginning with ‘>’) precedes them (Fig. 2A). Even though ESEfinder is an RNA analysis tool, only standard DNA notation is accepted (A, C, G and T, not U). The program will ignore any character other than A, C, G and T, including spaces and paragraph breaks. Both upper and lower cases are accepted but the output lines will be in upper case.
The user selects which matrices will be used, up to all four matrices simultaneously. For each matrix, the output is provided as a series of scores calculated in 1 nt increments. In the initial output window (Fig. 2B), only the ‘hits’ or ‘high-score motifs’ are displayed, giving the position of the first nucleotide, the sequence of the motif match, and the calculated score. A score is considered a high score when it is greater than the threshold value defined in the input page. Any score can be chosen as the cutoff value by selecting the ‘custom’ button and typing the desired value in the box. We suggest that for most routine analyses, users select the ‘default’ threshold values, above which we consider a score for a given sequence to be potentially significant. Our default threshold values are defined as the median of the highest scores for each sequence in a set of 30 randomly chosen 20 nt sequences (from the starting pool used for functional SELEX experiments). Such values are currently set as follows: SF2/ASF, 1.956; SC35, 2.383; SRp40, 2.670; SRp55, 2.676. Any refinements or updates will be incorporated as they become available. From the output window, the complete set of scores for the input sequence can be selected (Fig. 2C).
To facilitate the interpretation of the results and to standardize their representation, we implemented a graphic output of the query that is accessible from the output page (Fig. 2D). The query (exonic) sequence is reproduced along the x-axis. The presence of a high-score motif (above the selected threshold) is indicated by the color-coded bars. The height of the bars represents the motif scores, whereas their width indicates the length and position (6–8 nt).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONDESCRIPTIONDISCUSSIONREFERENCES |
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ESEfinder allows for the identification of putative ESEs and one of its most useful applications is the correct interpretation of the effects of disease-associated point mutations or polymorphisms. We have previously shown that ESEs predicted by this matrix-based approach tend to cluster in regions where natural enhancers have been experimentally mapped and are more frequent in exons than in introns (9,10). In a database of 50 human point mutations known to cause in vivo exon skipping, the majority reduced or eliminated at least one predicted ESE (12). Considering that we can currently search for putative ESEs using matrices for just four SR proteins, it is likely that a large fraction of skipping-associated mutations do indeed cause ESE disruption, and that a higher predictive value will be obtained when matrices for other relevant splicing factors become available. A computational approach (RESCUE-ESE) was recently described (7), in which putative ESE motifs are identified by comparing the frequency of hexamers in exons surrounded by ‘weak’ versus ‘strong’ splice sites. Several hexamer families enriched in the weak exons, which likely depend on enhancers for correct expression, were identified, and some of these overlap with the motifs defined by ESEfinder.
The ESEfinder matrices have been used to show that disruption of ESEs recognized by various SR proteins cause exon skipping in several genes (11–18). In some contexts, ESEfinder appears to be remarkably accurate. For example, using a BRCA1-derived three-exon minigene system, which is very responsive to point mutations within a critical ESE, we showed that when multiple SF2/ASF-dependent ESEs were substituted for each other or mutated, there was a strong correlation between exon-inclusion efficiency and the matrix scores (12,17). Furthermore, ESEfinder was used in combination with mutational analysis, in vitro and in vivo splicing, and site-specific UV-crosslinking experiments to demonstrate that the translationally silent, single-nucleotide difference between SMN1 and SMN2 disrupts an ESE, which in SMN1 is directly recognized by splicing factor SF2/ASF (17). The disruption of the SF2/ASF-dependent ESE causes inefficient SMN2 exon 7 inclusion. In the absence of SMN1, SMN2 is unable to produce enough full-length SMN protein, thus resulting in a spinal muscular atrophy phenotype. Finally, we exploited the degeneracy of the consensus motif, and used ESEfinder to design a second-site suppressor mutation that reconstituted the high-score motif and fully restored exon 7 inclusion in the SMN2 context in vivo and in vitro, as predicted (17). More than a dozen wild-type and mutant SF2/ASF heptamer motifs were tested in the SMN and BRCA1 systems (12,17). All of the motifs that maintained a high-score promoted exon inclusion in a manner roughly proportional to the motif score, even though, because of the degeneracy of the consensus motif, some of them did not share a single nucleotide. All of the motifs with below-threshold scores resulted in reduced levels of exon inclusion.
It should be emphasized, however, that the presence of a high-score motif in a sequence does not necessarily identify that sequence as a functional ESE, and that, in general, there is not a very strict quantitative correlation between numerical scores and ESE activity. Until stronger predictive algorithms are available, direct experimental evidence will remain necessary before safely concluding that a particular sequence can act as an ESE in its natural context. Conversely, the lack of a high-score motif does not imply that no ESEs are present. Several important variables, such as the local sequence context, the splice-site strengths, the position of the ESE along the exon and the presence of silencer elements, are likely to play a significant role in ESE activity. Furthermore, even mutations that abrogate genuine ESEs might not always exert a noticeable effect, because of the presence of redundant ESEs nearby. Finally, it should be noted that our matrices were defined in a mammalian system and reflect the sequence specificity of the human SR proteins. Their relevance to other species depends on the extent of conservation of each SR protein.
The development and refinement of reliable prediction tools for auxiliary splicing elements will have important implications for our ability to accurately identify the exon/intron structures of genes and predict their expression profile, to correctly interpret the effects of point mutations and/or polymorphisms, and to assess phenotypic risk.
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ACKNOWLEDGEMENTS |
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We thank the many users that sent us useful comments and suggestions which have been incorporated in the current release. We thank Xavier Roca for comments on the manuscript and Gengxin Chen for assistance. This work was supported by NIH grants GM42699 to A.R.K. and CA88351 and HG01696 to M.Q.Z.
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 D. Su, W. Zhang, Y. Yang, Y. Deng, Y. Ma, H. Song, and S. Zhang Mutation Screening and Association Study of the TSSK4 Gene in Chinese Infertile Men With Impaired Spermatogenesis J Androl, July 1, 2008; 29(4): 374 - 378. [Abstract] [Full Text] [PDF]
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E. Goina, N. Skoko, and F. Pagani Binding of DAZAP1 and hnRNPA1/A2 to an Exonic Splicing Silencer in a Natural BRCA1 Exon 18 Mutant Mol. Cell. Biol., June 1, 2008; 28(11): 3850 - 3860. [Abstract] [Full Text] [PDF]
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K D Hadfield, W G Newman, N L Bowers, A Wallace, C Bolger, A Colley, E McCann, D Trump, T Prescott, and D G R Evans Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis J. Med. Genet., June 1, 2008; 45(6): 332 - 339. [Abstract] [Full Text] [PDF]
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Z. Wang and C. B. Burge Splicing regulation: From a parts list of regulatory elements to an integrated splicing code RNA, May 1, 2008; 14(5): 802 - 813. [Abstract] [Full Text] [PDF]
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N. Gal-Mark, S. Schwartz, and G. Ast Alternative splicing of Alu exons--two arms are better than one Nucleic Acids Res., April 1, 2008; 36(6): 2012 - 2023. [Abstract] [Full Text] [PDF]
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 B. Hurtado, X. Munoz, M. C. Mulero, G. Navarro, P. Domenech, P. Garcia de Frutos, M. Perez-Riba, and N. Sala Functional characterization of twelve natural PROS1 mutations associated with anticoagulant protein S deficiency Haematologica, April 1, 2008; 93(4): 574 - 580. [Abstract] [Full Text] [PDF]
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C. Asang, I. Hauber, and H. Schaal Insights into the selective activation of alternatively used splice acceptors by the human immunodeficiency virus type-1 bidirectional splicing enhancer Nucleic Acids Res., March 1, 2008; 36(5): 1450 - 1463. [Abstract] [Full Text] [PDF]
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 A. Goren, E. Kim, M. Amit, R. Bochner, G. Lev-Maor, N. Ahituv, and G. Ast Alternative approach to a heavy weight problem Genome Res., February 1, 2008; 18(2): 214 - 220. [Abstract] [Full Text] [PDF]
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J. M. Gonzalez-Santos, H. Cao, R. C. Duan, and J. Hu Mutation in the splicing factor Hprp3p linked to retinitis pigmentosa impairs interactions within the U4/U6 snRNP complex Hum. Mol. Genet., January 15, 2008; 17(2): 225 - 239. [Abstract] [Full Text] [PDF]
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P. H. Lee and H. Shatkay F-SNP: computationally predicted functional SNPs for disease association studies Nucleic Acids Res., January 11, 2008; 36(suppl_1): D820 - D824. [Abstract] [Full Text] [PDF]
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Y. Zhang, A. Bertolino, L. Fazio, G. Blasi, A. Rampino, R. Romano, M.-L. T. Lee, T. Xiao, A. Papp, D. Wang, et al. Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory PNAS, December 18, 2007; 104(51): 20552 - 20557. [Abstract] [Full Text] [PDF]
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T. Kashima, N. Rao, C. J. David, and J. L. Manley hnRNP A1 functions with specificity in repression of SMN2 exon 7 splicing Hum. Mol. Genet., December 15, 2007; 16(24): 3149 - 3159. [Abstract] [Full Text] [PDF]
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R. H. Hovhannisyan and R. P. Carstens Heterogeneous Ribonucleoprotein M Is a Splicing Regulatory Protein That Can Enhance or Silence Splicing of Alternatively Spliced Exons J. Biol. Chem., December 14, 2007; 282(50): 36265 - 36274. [Abstract] [Full Text] [PDF]
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J. Blechingberg, S. Lykke-Andersen, T. H. Jensen, A. L. Jorgensen, and A. L. Nielsen Regulatory mechanisms for 3'-end alternative splicing and polyadenylation of the Glial Fibrillary Acidic Protein, GFAP, transcript Nucleic Acids Res., December 3, 2007; 35(22): 7636 - 7650. [Abstract] [Full Text] [PDF]
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E. Vela, J. M. Hilari, X. Roca, A. M. Munoz-Marmol, A. Ariza, and M. Isamat Multisite and bidirectional exonic splicing enhancer in CD44 alternative exon v3 RNA, December 1, 2007; 13(12): 2312 - 2323. [Abstract] [Full Text] [PDF]
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A Tomita-Mitchell, C L Maslen, C D Morris, V Garg, and E Goldmuntz GATA4 sequence variants in patients with congenital heart disease J. Med. Genet., December 1, 2007; 44(12): 779 - 783. [Abstract] [Full Text] [PDF]
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 P. H. Nissen, S. E. Christensen, L. Heickendorff, K. Brixen, and L. Mosekilde Molecular Genetic Analysis of the Calcium Sensing Receptor Gene in Patients Clinically Suspected to Have Familial Hypocalciuric Hypercalcemia: Phenotypic Variation and Mutation Spectrum in a Danish Population J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4373 - 4379. [Abstract] [Full Text] [PDF]
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J. Barbier, M. Dutertre, D. Bittencourt, G. Sanchez, L. Gratadou, P. de la Grange, and D. Auboeuf Regulation of H-ras Splice Variant Expression by Cross Talk between the p53 and Nonsense-Mediated mRNA Decay Pathways Mol. Cell. Biol., October 15, 2007; 27(20): 7315 - 7333. [Abstract] [Full Text] [PDF]
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Y.-F. Chang, W.-K. Chan, J. S. Imam, and M. F. Wilkinson Alternatively Spliced T-cell Receptor Transcripts Are Up-regulated in Response to Disruption of Either Splicing Elements or Reading Frame J. Biol. Chem., October 12, 2007; 282(41): 29738 - 29747. [Abstract] [Full Text] [PDF]
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J. Kralovicova and I. Vorechovsky Global control of aberrant splice-site activation by auxiliary splicing sequences: evidence for a gradient in exon and intron definition Nucleic Acids Res., October 8, 2007; 35(19): 6399 - 6413. [Abstract] [Full Text] [PDF]
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A. Aartsma-Rus and G.-J. B. van Ommen Antisense-mediated exon skipping: A versatile tool with therapeutic and research applications RNA, October 1, 2007; 13(10): 1609 - 1624. [Abstract] [Full Text] [PDF]
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H. Zhu, H. M. Tucker, K. E. Grear, J. F. Simpson, A. K. Manning, L. A. Cupples, and S. Estus A common polymorphism decreases low-density lipoprotein receptor exon 12 splicing efficiency and associates with increased cholesterol Hum. Mol. Genet., July 15, 2007; 16(14): 1765 - 1772. [Abstract] [Full Text] [PDF]
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R. I. Dogan, L. Getoor, W. J. Wilbur, and S. M. Mount SplicePort--An interactive splice-site analysis tool Nucleic Acids Res., July 13, 2007; 35(suppl_2): W285 - W291. [Abstract] [Full Text] [PDF]
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D. Das, T. A. Clark, A. Schweitzer, M. Yamamoto, H. Marr, J. Arribere, S. Minovitsky, A. Poliakov, I. Dubchak, J. E. Blume, et al. A correlation with exon expression approach to identify cis-regulatory elements for tissue-specific alternative splicing Nucleic Acids Res., July 10, 2007; (2007) gkm485v1. [Abstract] [Full Text] [PDF]
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S. Rossetti, M. B. Consugar, A. B. Chapman, V. E. Torres, L. M. Guay-Woodford, J. J. Grantham, W. M. Bennett, C. M. Meyers, D. L. Walker, K. Bae, et al. Comprehensive Molecular Diagnostics in Autosomal Dominant Polycystic Kidney Disease J. Am. Soc. Nephrol., July 1, 2007; 18(7): 2143 - 2160. [Abstract] [Full Text] [PDF]
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 R. B. Penn, V. E. Ortega, and E. R. Bleecker A Roadmap to functional genomics Physiol Genomics, June 19, 2007; 30(1): 82 - 88. [Abstract] [Full Text] [PDF]
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 W. Zhang, S. Zhang, C. Xiao, Y. Yang, and A Zhoucun Mutation screening of the FKBP6 gene and its association study with spermatogenic impairment in idiopathic infertile men Reproduction, February 1, 2007; 133(2): 511 - 516. [Abstract] [Full Text] [PDF]
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N. N. Singh, R. N. Singh, and E. J. Androphy Modulating role of RNA structure in alternative splicing of a critical exon in the spinal muscular atrophy genes Nucleic Acids Res., January 28, 2007; 35(2): 371 - 389. [Abstract] [Full Text] [PDF]
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M. Raponi, F. E. Baralle, and F. Pagani Reduced splicing efficiency induced by synonymous substitutions may generate a substrate for natural selection of new splicing isoforms: the case of CFTR exon 12 Nucleic Acids Res., January 28, 2007; 35(2): 606 - 613. [Abstract] [Full Text] [PDF]
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S. Li, L. Ma, H. Li, S. Vang, Y. Hu, L. Bolund, and J. Wang Snap: an integrated SNP annotation platform Nucleic Acids Res., January 12, 2007; 35(suppl_1): D707 - D710. [Abstract] [Full Text] [PDF]
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M. E. Hase, P. Yalamanchili, and N. Visa The Drosophila Heterogeneous Nuclear Ribonucleoprotein M Protein, HRP59, Regulates Alternative Splicing and Controls the Production of Its Own mRNA J. Biol. Chem., December 22, 2006; 281(51): 39135 - 39141. [Abstract] [Full Text] [PDF]
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 K. Suphapeetiporn, P. Kongkam, J. Tantivatana, T. Sinthuwiwat, S. Tongkobpetch, and V. Shotelersuk PTEN c.511C>T Nonsense Mutation in a BRRS Family Disrupts a Potential Exonic Splicing Enhancer and Causes Exon Skipping Jpn. J. Clin. Oncol., December 1, 2006; 36(12): 814 - 821. [Abstract] [Full Text] [PDF]
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V. K. Tran, Y. Takeshima, Z. Zhang, M. Yagi, A. Nishiyama, Y. Habara, and M. Matsuo Splicing analysis disclosed a determinant single nucleotide for exon skipping caused by a novel intraexonic four-nucleotide deletion in the dystrophin gene J. Med. Genet., December 1, 2006; 43(12): 924 - 930. [Abstract] [Full Text] [PDF]
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W. Szeszel-Fedorowicz, I. Talukdar, B. N. Griffith, C. M. Walsh, and L. M. Salati An Exonic Splicing Silencer Is Involved in the Regulated Splicing of Glucose 6-Phosphate Dehydrogenase mRNA J. Biol. Chem., November 10, 2006; 281(45): 34146 - 34158. [Abstract] [Full Text] [PDF]
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 P. Bhatti, D. M. Church, J. L. Rutter, J. P. Struewing, and A. J. Sigurdson Candidate Single Nucleotide Polymorphism Selection using Publicly Available Tools: A Guide for Epidemiologists Am. J. Epidemiol., October 15, 2006; 164(8): 794 - 804. [Abstract] [Full Text] [PDF]
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 D. S. Chandler, R. K. Singh, L. C. Caldwell, J. L. Bitler, and G. Lozano Genotoxic Stress Induces Coordinately Regulated Alternative Splicing of the p53 Modulators MDM2 and MDM4 Cancer Res., October 1, 2006; 66(19): 9502 - 9508. [Abstract] [Full Text] [PDF]
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P. J. Smith, C. Zhang, J. Wang, S. L. Chew, M. Q. Zhang, and A. R. Krainer An increased specificity score matrix for the prediction of SF2/ASF-specific exonic splicing enhancers Hum. Mol. Genet., August 15, 2006; 15(16): 2490 - 2508. [Abstract] [Full Text] [PDF]
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E. Buratti, M. Baralle, and F. E. Baralle Defective splicing, disease and therapy: searching for master checkpoints in exon definition Nucleic Acids Res., July 19, 2006; 34(12): 3494 - 3510. [Abstract] [Full Text] [PDF]
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J. Chen, A. Rattner, and J. Nathans Effects of L1 retrotransposon insertion on transcript processing, localization and accumulation: lessons from the retinal degeneration 7 mouse and implications for the genomic ecology of L1 elements Hum. Mol. Genet., July 1, 2006; 15(13): 2146 - 2156. [Abstract] [Full Text] [PDF]
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H.-Y. Huang, C.-H. Chien, K.-H. Jen, and H.-D. Huang RegRNA: an integrated web server for identifying regulatory RNA motifs and elements. Nucleic Acids Res., July 1, 2006; 34(Web Server issue): W429 - W434. [Abstract] [Full Text] [PDF]
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H.-Y. Yuan, J.-J. Chiou, W.-H. Tseng, C.-H. Liu, C.-K. Liu, Y.-J. Lin, H.-H. Wang, A. Yao, Y.-T. Chen, and C.-N. Hsu FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization. Nucleic Acids Res., July 1, 2006; 34(Web Server issue): W635 - W641. [Abstract] [Full Text] [PDF]
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S. Spena, M. L. Tenchini, and E. Buratti Cryptic splice site usage in exon 7 of the human fibrinogen B{beta}-chain gene is regulated by a naturally silent SF2/ASF binding site within this exon RNA, June 1, 2006; 12(6): 948 - 958. [Abstract] [Full Text] [PDF]
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A Warrington, A R Vieira, K Christensen, I M Orioli, E E Castilla, P A Romitti, and J C Murray Genetic evidence for the role of loci at 19q13 in cleft lip and palate. J. Med. Genet., June 1, 2006; 43(6): e26 - e26. [Abstract] [Full Text] [PDF]
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R. Agrawal and G. D. Stormo Using mRNAs lengths to accurately predict the alternatively spliced gene products in Caenorhabditis elegans Bioinformatics, May 15, 2006; 22(10): 1239 - 1244. [Abstract] [Full Text] [PDF]
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X. Zhong, J. R. Liu, J. W. Kyle, D. A. Hanck, and W. S. Agnew A profile of alternative RNA splicing and transcript variation of CACNA1H, a human T-channel gene candidate for idiopathic generalized epilepsies Hum. Mol. Genet., May 1, 2006; 15(9): 1497 - 1512. [Abstract] [Full Text] [PDF]
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 T. Walsh, S. Casadei, K. H. Coats, E. Swisher, S. M. Stray, J. Higgins, K. C. Roach, J. Mandell, M. K. Lee, S. Ciernikova, et al. Spectrum of Mutations in BRCA1, BRCA2, CHEK2, and TP53 in Families at High Risk of Breast Cancer JAMA, March 22, 2006; 295(12): 1379 - 1388. [Abstract] [Full Text] [PDF]
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J. Vadolas, M. Nefedov, H. Wardan, S. Mansooriderakshan, L. Voullaire, D. Jamsai, R. Williamson, and P. A. Ioannou Humanized beta-Thalassemia Mouse Model Containing the Common IVSI-110 Splicing Mutation J. Biol. Chem., March 17, 2006; 281(11): 7399 - 7405. [Abstract] [Full Text] [PDF]
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A. Disset, C.F. Bourgeois, N. Benmalek, M. Claustres, J. Stevenin, and S. Tuffery-Giraud An exon skipping-associated nonsense mutation in the dystrophin gene uncovers a complex interplay between multiple antagonistic splicing elements Hum. Mol. Genet., March 15, 2006; 15(6): 999 - 1013. [Abstract] [Full Text] [PDF]
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N. Elleuch, C. Depienne, A. Benomar, A. M. O. Hernandez, X. Ferrer, B. Fontaine, D. Grid, C.M.E. Tallaksen, R. Zemmouri, G. Stevanin, et al. Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia Neurology, March 14, 2006; 66(5): 654 - 659. [Abstract] [Full Text] [PDF]
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S.-N. Grellscheid and C. W. J. Smith An Apparent Pseudo-Exon Acts both as an Alternative Exon That Leads to Nonsense-Mediated Decay and as a Zero-Length Exon. Mol. Cell. Biol., March 1, 2006; 26(6): 2237 - 2246. [Abstract] [Full Text] [PDF]
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