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AG-dependent 3′-splice sites are predisposed to aberrant splicing due to a mutation at the first nucleotide of an exon

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Nucleic Acids Research

Oxford University Press

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      Abstract

      In pre-mRNA splicing, a conserved AG/G at the 3′-splice site is recognized by U2AF35. A disease-causing mutation abrogating the G nucleotide at the first position of an exon (E+1) causes exon skipping in GH1, FECH and EYA1, but not in LPL or HEXA. Knockdown of U2AF35 enhanced exon skipping in GH1 and FECH. RNA-EMSA revealed that wild-type FECH requires U2AF35 but wild-type LPL does not. A series of artificial mutations in the polypyrimidine tracts of GH1, FECH, EYA1, LPL and HEXA disclosed that a stretch of at least 10–15 pyrimidines is required to ensure normal splicing in the presence of a mutation at E+1. Analysis of nine other disease-causing mutations at E+1 detected five splicing mutations. Our studies suggest that a mutation at the AG-dependent 3′-splice site that requires U2AF35 for spliceosome assembly causes exon skipping, whereas one at the AG-independent 3′-splice site that does not require U2AF35 gives rise to normal splicing. The AG-dependence of the 3′-splice site that we analyzed in disease-causing mutations at E+1 potentially helps identify yet unrecognized splicing mutations at E+1.

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      Most cited references 34

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      Mechanisms of alternative pre-messenger RNA splicing.

       Justin Black (2002)
      Alternative pre-mRNA splicing is a central mode of genetic regulation in higher eukaryotes. Variability in splicing patterns is a major source of protein diversity from the genome. In this review, I describe what is currently known of the molecular mechanisms that control changes in splice site choice. I start with the best-characterized systems from the Drosophila sex determination pathway, and then describe the regulators of other systems about whose mechanisms there is some data. How these regulators are combined into complex systems of tissue-specific splicing is discussed. In conclusion, very recent studies are presented that point to new directions for understanding alternative splicing and its mechanisms.
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        ESEfinder: A web resource to identify exonic splicing enhancers.

        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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          Predictive identification of exonic splicing enhancers in human genes.

          Specific short oligonucleotide sequences that enhance pre-mRNA splicing when present in exons, termed exonic splicing enhancers (ESEs), play important roles in constitutive and alternative splicing. A computational method, RESCUE-ESE, was developed that predicts which sequences have ESE activity by statistical analysis of exon-intron and splice site composition. When large data sets of human gene sequences were used, this method identified 10 predicted ESE motifs. Representatives of all 10 motifs were found to display enhancer activity in vivo, whereas point mutants of these sequences exhibited sharply reduced activity. The motifs identified enable prediction of the splicing phenotypes of exonic mutations in human genes.
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            Author and article information

            Affiliations
            Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan
            Author notes
            *To whom correspondence should be addressed. Tel: +81 52 744 2446; Fax: +81 52 744 2449; Email: ohnok@ 123456med.nagoya-u.ac.jp
            Journal
            Nucleic Acids Res
            nar
            nar
            Nucleic Acids Research
            Oxford University Press
            0305-1048
            1362-4962
            May 2011
            May 2011
            2 February 2011
            2 February 2011
            : 39
            : 10
            : 4396-4404
            3105431
            21288883
            10.1093/nar/gkr026
            gkr026
            © The Author(s) 2011. Published by Oxford University Press.

            This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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            Pages: 9
            Categories
            RNA

            Genetics

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