Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

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

Nature Reviews Genetics volume 8, pages 749–761 (2007)Cite this article

Key Points

  • Cis-acting elements within exons and introns make up a splicing code that is required for efficient pre-mRNA splicing. A large fraction of non-synonymous exonic mutations cause disease due to disrupted splicing rather than the predicted amino-acid change.

  • Splicing affects disease by three general mechanisms: as a direct cause, as a modifier of severity and as a determinant of disease susceptibility. In all three cases, the pathogenic splicing effect can be in cis affecting the 'disease gene' or in trans resulting from alterations of the splicing environment.

  • Genome-wide analysis of alternative splicing using splicing microarrays has identified coordinated networks of splicing regulation. Computational analysis of co-regulated exons has identified motifs of known RNA binding proteins as well as novel motifs.

  • Pathogenesis of a growing number of microsatellite expansion disorders is known to involve the expression of repeat-containing RNAs that have a toxic effect by disrupting regulators of alternative splicing.

  • Analysis of 50 cancer-relevant genes that are thought to be well characterized has found that two-thirds of these genes express novel isoforms in normal tissues, and that the novel isoform is predominant for 40% of these genes. This finding illustrates the need to identify predominant splice variants for the cells and tissues of interest.

  • The oncogenic activities of two genes are enhanced by the splicing factor SF2/ASF through induction of oncogenic alternatively spliced isoforms.

  • Splicing-based therapeutic approaches are directed at either reversing or circumventing the deleterious splicing pattern.

Abstract

Human genes contain a dense array of diverse cis-acting elements that make up a code required for the expression of correctly spliced mRNAs. Alternative splicing generates a highly dynamic human proteome through networks of coordinated splicing events. Cis- and trans-acting mutations that disrupt the splicing code or the machinery required for splicing and its regulation have roles in various diseases, and recent studies have provided new insights into the mechanisms by which these effects occur. An unexpectedly large fraction of exonic mutations exhibit a primary pathogenic effect on splicing. Furthermore, normal genetic variation significantly contributes to disease severity and susceptibility by affecting splicing efficiency.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The splicing code.
Figure 2: Therapeutic approaches that utilize splicing.

Similar content being viewed by others

References

  1. Johnson, J. M. et al. Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays. Science 302, 2141–2144 (2003). One of the early splicing microarray papers, in which exon–exon junctions from 10,000 human genes were probed using RNA from 52 different human tissues.

    Article  CAS  PubMed  Google Scholar 

  2. Black, D. L. Mechanisms of alternative pre-messenger RNA splicing. Annu. Rev. Biochem. 27, 27–48 (2003).

    Google Scholar 

  3. Modrek, B. & Lee, C. A genomic view of alternative splicing. Nature Genet. 30, 13–19 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Lewis, B. P., Green, R. E. & Brenner, S. E. Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans. Proc. Natl Acad. Sci. USA 100, 189–192 (2003). A quantitative computational analysis demonstrating that one-third of alternatively spliced transcripts contain a premature termination codon and are potentially subject to NMD.

    Article  CAS  PubMed  Google Scholar 

  5. Blencowe, B. J. Alternative splicing: new insights from global analyses. Cell 126, 37–47 (2006). An outstanding review of the application of splicing microarrays to obtain a global perspective on the regulation of alternative splicing.

    Article  CAS  PubMed  Google Scholar 

  6. Burge, C. B., Tuschl, T. & Sharp, P. A. Splicing of precursors to mRNAs by the spliceosomes. in The RNA World (eds Gesteland, R. F., Cech, T. R. & Atkins, J. F.) 525–560 (Cold Spring Harbor Laboratory Press, New York, 1999).

    Google Scholar 

  7. Cartegni, L., Chew, S. L. & Krainer, A. R. Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nature Rev. Genet. 3, 285–298 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Fairbrother, W. G., Yeh, R. F., Sharp, P. A. & Burge, C. B. Predictive identification of exonic splicing enhancers in human genes. Science 297, 1007–1013 (2002). An early use of computational analysis (RESCUE-ESE) to identify sequence motifs within exons. Functional analysis using minigene reporters demonstrated that most of the computationally identified sequences enhanced exon inclusion.

    Article  CAS  PubMed  Google Scholar 

  9. Zhang, X. H. & Chasin, L. A. Computational definition of sequence motifs governing constitutive exon splicing. Genes Dev. 18, 1241–1250 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fairbrother, W. G. et al. RESCUE-ESE identifies candidate exonic splicing enhancers in vertebrate exons. Nucleic Acids Res. 32, W187–W190 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Goren, A. et al. Comparative analysis identifies exonic splicing regulatory sequences — the complex definition of enhancers and silencers. Mol. Cell 22, 769–781 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Smith, P. J. et al. An increased specificity score matrix for the prediction of SF2/ASF-specific exonic splicing enhancers. Hum. Mol. Genet. 15, 2490–2508 (2006). ESEfinder is a commonly used program to identify binding sites for specific SR proteins within exons.

    Article  CAS  PubMed  Google Scholar 

  13. Pagani, F. et al. New type of disease causing mutations: the example of the composite exonic regulatory elements of splicing in CFTR exon 12. Hum. Mol. Genet. 12, 1111–1120 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Kanopka, A., Muhlemann, O. & Akusjarvi, G. Inhibition by SR proteins of splicing of a regulated adenovirus pre-mRNA. Nature 381, 535–538 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Ule, J. et al. An RNA map predicting NOVA-dependent splicing regulation. Nature 444, 580–586 (2006). Combined computational and biochemical analyses demonstrated that the position of the NOVA binding site relative to the exon is predictive of whether NOVA enhances or represses the alternative splicing event.

    Article  CAS  PubMed  Google Scholar 

  16. Matlin, A. J., Clark, F. & Smith, C. W. Understanding alternative splicing: towards a cellular code. Nature Rev. Mol. Cell Biol. 6, 386–398 (2005).

    Article  CAS  Google Scholar 

  17. Polydorides, A. D., Okano, H. J., Yang, Y. Y., Stefani, G. & Darnell, R. B. A brain-enriched polypyrimidine tract-binding protein antagonizes the ability of NOVA to regulate neuron-specific alternative splicing. Proc. Natl Acad. Sci. USA 97, 6350–6355 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ho, T. H. et al. Muscleblind proteins regulate alternative splicing. EMBO J. 23, 3103–3112 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Charlet-B., N., Logan, P., Singh, G. & Cooper, T. A. Dynamic antagonism between ETR-3 and PTB regulates cell type-specific alternative splicing. Mol. Cell 9, 649–658 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Jin, Y. et al. A vertebrate RNA-binding protein FOX-1 regulates tissue-specific splicing via the pentanucleotide GCAUG. EMBO J. 22, 905–912 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Izquierdo, J. M. et al. Regulation of Fas alternative splicing by antagonistic effects of TIA-1 and PTB on exon definition. Mol. Cell 19, 475–484 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Roy, M., Xu, Q. & Lee, C. Evidence that public database records for many cancer-associated genes reflect a splice form found in tumors and lack normal splice forms. Nucleic Acids Res. 33, 5026–5033 (2005). This work demonstrated that the normal isoforms of a panel of 50 cancer-related genes were underrepresented in GenBank because 70% of GenBank entries for these genes are derived from tumour samples. The authors found that the predominating isoforms in normal tissues for many of these genes were novel.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhong, X., Liu, J. R., Kyle, J. W., Hanck, D. A. & Agnew, W. S. A profile of alternative RNA splicing and transcript variation of CACNA1H, a human T-channel gene candidate for idiopathic generalized epilepsies. Hum. Mol. Genet. 15, 1497–1512 (2006). Tour de force identification and functional characterization of the large number of protein isoforms that are expressed from the human T-type calcium channel gene. An extensive range of biophysical properties among the isoforms is contrasted with the fact that only a few have been used for functional analysis of mutants associated with epilepsy.

    Article  CAS  PubMed  Google Scholar 

  24. Krawczak, M., Reiss, J. & Cooper, D. N. The mutational spectrum of single base-pair substitutions in messenger RNA splice junctions of human genes — causes and consequences. Hum. Genet. 90, 41–54 (1992).

    Article  CAS  PubMed  Google Scholar 

  25. Pagani, F. & Baralle, F. E. Genomic variants in exons and introns: identifying the splicing spoilers. Nature Rev. Genet. 5, 389–396 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Pagenstecher, C. et al. Aberrant splicing in MLH1 and MSH2 due to exonic and intronic variants. Hum. Genet. 119, 9–22 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Lopez-Bigas, N., Audit, B., Ouzounis, C., Parra, G. & Guigo, R. Are splicing mutations the most frequent cause of hereditary disease? FEBS Lett. 579, 1900–1903 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Stenson, P. D. et al. Human Gene Mutation Database (HGMD): 2003 update. Hum. Mutat. 21, 577–581 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Pagani, F., Raponi, M. & Baralle, F. E. Synonymous mutations in CFTR exon 12 affect splicing and are not neutral in evolution. Proc. Natl Acad. Sci. USA 102, 6368–6372 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jurica, M. S. & Moore, M. J. Pre-mRNA splicing: awash in a sea of proteins. Mol. Cell 12, 5–14 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Briese, M., Esmaeili, B. & Sattelle, D. B. Is spinal muscular atrophy the result of defects in motor neuron processes? Bioessays 27, 946–957 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Mordes, D. et al. Pre-mRNA splicing and retinitis pigmentosa. Mol. Vis. 12, 1259–1271 (2006).

    CAS  PubMed  Google Scholar 

  33. Winkler, C. et al. Reduced U snRNP assembly causes motor axon degeneration in an animal model for spinal muscular atrophy. Genes Dev. 19, 2320–2330 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chakarova, C. F. et al. Mutations in HPRP3, a third member of pre-mRNA splicing factor genes, implicated in autosomal dominant retinitis pigmentosa. Hum. Mol. Genet. 11, 87–92 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Vithana, E. N. et al. A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11). Mol. Cell 8, 375–381 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. McKie, A. B. et al. Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13). Hum. Mol. Genet. 10, 1555–1562 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Goldstone, A. P. Prader–Willi syndrome: advances in genetics, pathophysiology and treatment. Trends Endocrinol. Metab. 15, 12–20 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Cavaille, J. et al. Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization. Proc. Natl Acad. Sci. USA 97, 14311–14316 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kishore, S. & Stamm, S. The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C. Science 311, 230–232 (2006). This work demonstrated that a snoRNA regulates splicing of the serotonin receptor by binding to the pre-mRNA. Loss of this RNA correlates with altered splicing in Prader–Willi syndrome.

    Article  CAS  PubMed  Google Scholar 

  40. Gatchel, J. R. & Zoghbi, H. Y. Diseases of unstable repeat expansion: mechanisms and common principles. Nature Rev. Genet. 6, 743–755 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Lalioti, M. D. et al. Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy. Nature 386, 847–851 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Ranum, L. P. & Cooper, T. A. RNA-mediated neuromuscular disorders. Annu. Rev. Neurosci. 29, 259–277 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Cho, D. H. & Tapscott, S. J. Myotonic dystrophy: emerging mechanisms for DM1 and DM2. Biochim. Biophys. Acta 1772, 195–204 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Wang, G. S., Kearney, D. L., De Biasi, M., Taffet, G. & Cooper, T. A. Elevated CUG-BP1 is an early event in an inducible heart-specific mouse model of myotonic dystrophy. J. Clin. Invest. (in the press).

  45. Mahadevan, M. S. et al. Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy. Nature Genet. 38, 1066–1070 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Osborne, R. J. & Thornton, C. A. RNA-dominant diseases. Hum. Mol. Genet. 15, R162–R169 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Lin, X. et al. Failure of MBNL1-dependent postnatal splicing transitions in myotonic dystrophy. Hum. Mol. Genet. 15, 2087–2097 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Ladd, A. N., Stenberg, M. G., Swanson, M. S. & Cooper, T. A. Dynamic balance between activation and repression regulates pre-mRNA alternative splicing during heart development. Dev. Dyn. 233, 783–793 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Kuyumcu-Martinez, M. N., Wang, G. S. & Cooper, T. A. Increased steady state levels of CUG-BP1 in myotonic dystrophy 1 are due to PKC-mediated hyperphosphorylation. Mol. Cell (in the press).

  50. Timchenko, N. A. et al. RNA CUG repeats sequester CUGBP1 and alter protein levels and activity of CUGBP1. J. Biol. Chem. 276, 7820–7826 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Stephens, J. C. et al. Haplotype variation and linkage disequilibrium in 313 human genes. Science 293, 489–493 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Krawczak, M. et al. Single base-pair substitutions in exon–intron junctions of human genes: nature, distribution, and consequences for mRNA splicing. Hum. Mutat. 28, 150–158 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Kralovicova, J., Houngninou-Molango, S., Kramer, A. & Vorechovsky, I. Branch site haplotypes that control alternative splicing. Hum. Mol. Genet. 13, 3189–3202 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Chisa, J. L. & Burke, D. T. Mammalian mRNA splice-isoform selection is tightly controlled. Genetics 175, 1079–1087 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hull, J. et al. Identification of common genetic variation that modulates alternative splicing. PLoS Genet. 3, e99 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Marden, J. H. Quantitative and evolutionary biology of alternative splicing: how changing the mix of alternative transcripts affects phenotypic plasticity and reaction norms. Heredity 27 September 2006 (doi: 10.1038/sj.hdy.6800904).

    Article  PubMed  CAS  Google Scholar 

  57. Nissim-Rafinia, M. & Kerem, B. Splicing regulation as a potential genetic modifier. Trends Genet. 18, 123–127 (2002). An early analysis of the role of splicing as a genetic modifier of disease.

    Article  CAS  PubMed  Google Scholar 

  58. Noone, P. G. & Knowles, M. R. 'CFTR-opathies': disease phenotypes associated with cystic fibrosis transmembrane regulator gene mutations. Respir. Res. 2, 328–332 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Steiner, B., Truninger, K., Sanz, J., Schaller, A. & Gallati, S. The role of common single-nucleotide polymorphisms on exon 9 and exon 12 skipping in nonmutated CFTR alleles. Hum. Mutat. 24, 120–129 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Nielsen, K. B. et al. Seemingly neutral polymorphic variants may confer immunity to splicing-inactivating mutations: a synonymous SNP in exon 5 of MCAD protects from deleterious mutations in a flanking exonic splicing enhancer. Am. J. Hum. Genet. 80, 416–432 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hims, M. M. et al. Therapeutic potential and mechanism of kinetin as a treatment for the human splicing disease familial dysautonomia. J. Mol. Med. 85, 149–161 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Cuajungco, M. P. et al. Tissue-specific reduction in splicing efficiency of IKBKAP due to the major mutation associated with familial dysautonomia. Am. J. Hum. Genet. 72, 749–758 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Axelrod, F. B. Familial dysautonomia: a review of the current pharmacological treatments. Expert Opin. Pharmacother. 6, 561–567 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Buchner, D. A., Trudeau, M. & Meisler, M. H. SCNM1, a putative RNA splicing factor that modifies disease severity in mice. Science 301, 967–969 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Farrall, M. & Morris, A. P. Gearing up for genome-wide gene-association studies. Hum. Mol. Genet. 14, R157–R162 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Brasch-Andersen, C. et al. Significant linkage to chromosome 12q24.32–q24.33 and identification of SFRS8 as a possible asthma susceptibility gene. Thorax 61, 874–879 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Bracco, L. & Kearsey, J. The relevance of alternative RNA splicing to pharmacogenomics. Trends Biotechnol. 21, 346–353 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Heinzen, E. L. et al. Nova2 Interacts with a cis-acting polymorphism to influence the proportions of drug-responsive splice variants of SCN1A. Am. J. Hum. Genet. 80, 876–883 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Skotheim, R. I. & Nees, M. Alternative splicing in cancer: noise, functional, or systematic? Int. J. Biochem. Cell Biol. 39, 1432–1449 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Venables, J. P. Unbalanced alternative splicing and its significance in cancer. Bioessays 28, 378–386 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Srebrow, A. & Kornblihtt, A. R. The connection between splicing and cancer. J. Cell Sci. 119, 2635–2641 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Karni, R. et al. The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nature Struct. Mol. Biol. 14, 185–193 (2007). This work demonstrated that the splicing factor SF2/ASF acts as a proto-oncogene.

    Article  CAS  Google Scholar 

  73. Ghigna, C. et al. Cell motility is controlled by SF2/ASF through alternative splicing of the RON protooncogene. Mol. Cell 20, 881–890 (2005). This paper identified the RON tyrosine kinase receptor as a target of SF2/ASF and presents a clear demonstration that increased SF2/ASF expression promotes an epithelial-to-mesenchymal transition through altered RON splicing.

    Article  CAS  PubMed  Google Scholar 

  74. Sjoblom, T. et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–274 (2006).

    Article  PubMed  CAS  Google Scholar 

  75. Stickeler, E., Kittrell, F., Medina, D. & Berget, S. M. Stage-specific changes in SR splicing factors and alternative splicing in mammary tumorigenesis. Oncogene 18, 3574–3582 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Huang, Y. & Steitz, J. A. SRprises along a messenger's journey. Mol. Cell 17, 613–615 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Li, X. & Manley, J. L. Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability. Cell 122, 365–378 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Segal, E., Friedman, N., Kaminski, N., Regev, A. & Koller, D. From signatures to models: understanding cancer using microarrays. Nature Genet. 37, S38–S45 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Gardina, P. J. et al. Alternative splicing and differential gene expression in colon cancer detected by a whole genome exon array. BMC Genomics 7, 325 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Relogio, A. et al. Alternative splicing microarrays reveal functional expression of neuron-specific regulators in Hodgkin lymphoma cells. J. Biol. Chem. 280, 4779–4784 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Zhang, C. et al. Profiling alternatively spliced mRNA isoforms for prostate cancer classification. BMC Bioinformatics 7, 202 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Berget, S. M. Exon recognition in vertebrate splicing. J. Biol. Chem. 270, 2411–2414 (1995).

    Article  CAS  PubMed  Google Scholar 

  83. Steward, R. E., MacArthur, M. W., Laskowski, R. A. & Thornton, J. M. Molecular basis of inherited diseases: a structural perspective. Trends Genet. 19, 505–513 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Consortium, E. P. The ENCODE (ENCyclopedia Of DNA Elements) Project. Science 306, 636–640 (2004).

    Article  CAS  Google Scholar 

  85. Pan, Q. et al. Revealing global regulatory features of mammalian alternative splicing using a quantitative microarray platform. Mol. Cell 16, 929–941 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Ule, J. et al. Nova regulates brain-specific splicing to shape the synapse. Nature Genet. 37, 844–852 (2005). Splicing microarray analyses of alternative splicing differences in NOVA knockout mice identified enrichment for genes involved in synaptic plasticity.

    Article  CAS  PubMed  Google Scholar 

  87. Ip, J. Y. et al. Global analysis of alternative splicing during T-cell activation. RNA 13, 563–572 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sugnet, C. W. et al. Unusual intron conservation near tissue-regulated exons found by splicing microarrays. PLoS Comput. Biol. 2, e4 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Hagerman, P. J. & Hagerman, R. J. The fragile-X premutation: a maturing perspective. Am. J. Hum. Genet. 74, 805–816 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Tassone, F. et al. Elevated FMR1 mRNA in premutation carriers is due to increased transcription. RNA 13, 555–562 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Willemsen, R. et al. The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome. Hum. Mol. Genet. 12, 949–959 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Jin, P. et al. RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila. Neuron 39, 739–747 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Iwahashi, C. K. et al. Protein composition of the intranuclear inclusions of FXTAS. Brain 129, 256–271 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. Ikeda, Y. et al. Spinocerebellar ataxia type 8: molecular genetic comparisons and haplotype analysis of 37 families with ataxia. Am. J. Hum. Genet. 75, 3–16 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Moseley, M. L. et al. Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nature Genet. 38, 758–769 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Margolis, R. L., Rudnicki, D. D. & Holmes, S. E. Huntington's disease like-2: review and update. Acta Neurol. Taiwan 14, 1–8 (2005).

    PubMed  Google Scholar 

  97. Rudnicki, D. D. et al. Huntington's disease-like 2 is associated with CUG repeat-containing RNA foci. Ann. Neurol. 61, 272–282 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Soret, J., Gabut, M. & Tazi, J. SR proteins as potential targets for therapy. Prog. Mol. Subcell. Biol. 44, 65–87 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Xiao, S. H. & Manley, J. L. Phosphorylation of the ASF/SF2 RS domain affects both protein–protein and protein–RNA interactions and is necessary for splicing. Genes Dev. 11, 334–344 (1997).

    Article  CAS  PubMed  Google Scholar 

  100. Graveley, B. R. Sorting out the complexity of SR protein functions. RNA 6, 1197–1211 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Orengo, J. P., Bundman, D. & Cooper, T. A. A bichromatic fluorescent reporter for cell-based screens of alternative splicing. Nucleic Acids Res. 34, e148 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Bonano, V. I., Oltean, S., Brazas, R. M. & Garcia-Blanco, M. A. Imaging the alternative silencing of FGFR2 exon IIIb in vivo. RNA 12, 2073–2079 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Garcia-Blanco, M. A. Alternative splicing: therapeutic target and tool. Prog. Mol. Subcell. Biol. 44, 47–64 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Hua, Y., Vickers, T. A., Baker, B. F., Bennett, C. F. & Krainer, A. R. Enhancement of SMN2 exon 7 inclusion by antisense oligonucleotides targeting the exon. PLoS Biol. 5, e73 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Cartegni, L. & Krainer, A. R. Correction of disease-associated exon skipping by synthetic exon-specific activators. Nature Struct. Biol. 10, 120–125 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. Skordis, L. A., Dunckley, M. G., Yue, B., Eperon, I. C. & Muntoni, F. Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts. Proc. Natl Acad. Sci. USA 100, 4114–4119 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Larriba, S. et al. Testicular CFTR splice variants in patients with congenital absence of the vas deferens. Hum. Mol. Genet. 7, 1739–1743 (1998).

    Article  CAS  PubMed  Google Scholar 

  108. Niksic, M., Romano, M., Buratti, E., Pagani, F. & Baralle, F. E. Functional analysis of cis-acting elements regulating the alternative splicing of human CFTR exon 9. Hum. Mol. Genet. 8, 2339–2349 (1999).

    Article  CAS  PubMed  Google Scholar 

  109. Chiba-Falek, O. et al. The molecular basis of disease variability among cystic fibrosis patients carrying the 3849+10 kb C→T mutation. Genomics 53, 276–283 (1998).

    Article  CAS  PubMed  Google Scholar 

  110. Graham, R. R. et al. A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nature Genet. 38, 550–555 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Ueda, H. et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506–511 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Atz, M. E., Rollins, B. & Vawter, M. P. NCAM1 association study of bipolar disorder and schizophrenia: polymorphisms and alternatively spliced isoforms lead to similarities and differences. Psychiatr. Genet. 17, 55–67 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Law, A. J., Kleinman, J. E., Weinberger, D. R. & Weickert, C. S. Disease-associated intronic variants in the ERBB4 gene are related to altered ERBB4 splice-variant expression in the brain in schizophrenia. Hum. Mol. Genet. 16, 129–141 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Mango, R. et al. In vivo and in vitro studies support that a new splicing isoform of OLR1 gene is protective against acute myocardial infarction. Circ. Res. 97, 152–158 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Bonnevie-Nielsen, V. et al. Variation in antiviral 2′,5′-oligoadenylate synthetase (2′5′AS) enzyme activity is controlled by a single-nucleotide polymorphism at a splice-acceptor site in the OAS1 gene. Am. J. Hum. Genet. 76, 623–633 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Komamura, K. et al. The role of a common TNNT2 polymorphism in cardiac hypertrophy. J. Hum. Genet. 49, 129–133 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Laitinen, T. et al. Characterization of a common susceptibility locus for asthma-related traits. Science 304, 300–304 (2004).

    Article  CAS  PubMed  Google Scholar 

  118. Caffrey, T. M., Joachim, C., Paracchini, S., Esiri, M. M. & Wade-Martins, R. Haplotype-specific expression of exon 10 at the human MAPT locus. Hum. Mol. Genet. 15, 3529–3537 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. Stanton, T. et al. A high-frequency polymorphism in exon 6 of the CD45 tyrosine phosphatase gene (PTPRC) resulting in altered isoform expression. Proc. Natl Acad. Sci. USA 100, 5997–6002 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Jacobsen, M. et al. A point mutation in PTPRC is associated with the development of multiple sclerosis. Nature Genet. 26, 495–499 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Thude, H., Hundrieser, J., Wonigeit, K. & Schwinzer, R. A point mutation in the human CD45 gene associated with defective splicing of exon A. Eur. J. Immunol. 25, 2101–2106 (1995).

    Article  CAS  PubMed  Google Scholar 

  122. Zhu, H. et al. A common polymorphism decreases low-density lipoprotein receptor exon 12 splicing efficiency and associates with increased cholesterol. Hum. Mol. Genet. 16, 1765–1772 (2007).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

A great deal of outstanding work has been published on the topics covered in this Review, and space limitations prevent mention of all important contributions. The work in our laboratory is supported by the US National Institutes of Health (NIH) and the Muscular Dystrophy Association (USA).

Author information

Authors and Affiliations

  1. Departments of Pathology, Baylor College of Medicine, Houston, 77030, Texas, USA

    Guey-Shin Wang & Thomas A. Cooper

  2. Department of Molecular and Cellular Biology, Baylor College of Medicine,

    Thomas A. Cooper

Authors
  1. Guey-Shin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas A. Cooper
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas A. Cooper.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

OMIM

cystic fibrosis

familial dysautonomia

FXTAS

HDL2

Huntington disease

myotonic dystrophy

oculopharyngeal muscular dystrophy

Prader–Willi Syndrome

retinitis pigmentosa

SCA8

spinal muscular atrophy

spinocerebellar ataxias

FURTHER INFORMATION

Alternative Splicing Database Project

Alternative Splicing Annotation Project database

Cooper Laboratory homepage

ESE finder

Human Gene Mutation Database

RESCUE-ESE Web Server

RetNet: Summaries of Genes and Loci Causing Retinal Diseases

Spidey mRNA-to-genomic alignment

Glossary

Spliceosome

The basal splicing machinery, which is made up of 5 small nuclear ribonucleoproteins (snRNPs) and more than 150 additional proteins.

Pseudoexons

Intronic sequences that fortuitously resemble exons because of matches to 3′ and 5′ splice sites that are not normally spliced.

snRNPs

Complexes of small nuclear RNAs (snRNAs) associated with ∼20 proteins. The snRNA components of snRNPs form the catalytic core of the spliceosome.

SR proteins

A family of 11 highly conserved proteins that were originally identified as being required for constitutive and alternative splicing.

hnRNPs

Heterogeneous nuclear ribonucleoproteins are an abundant class of predominantly nuclear RNA binding proteins that contain an RNA recognition motif (RRM) type of RNA binding domain.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, GS., Cooper, T. Splicing in disease: disruption of the splicing code and the decoding machinery. Nat Rev Genet 8, 749–761 (2007). https://doi.org/10.1038/nrg2164

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg2164

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing