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      Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1.

      Nature genetics

      Base Sequence, Cell Line, Cyclic AMP Response Element-Binding Protein, DNA Mutational Analysis, Exons, Humans, Introns, Models, Genetic, Molecular Sequence Data, Muscular Atrophy, Spinal, genetics, Mutagenesis, Site-Directed, Mutation, Nerve Tissue Proteins, chemistry, Nuclear Proteins, Ultraviolet Rays, Phenotype, Point Mutation, Protein Biosynthesis, RNA, metabolism, RNA Splicing, RNA, Messenger, RNA-Binding Proteins, Reverse Transcriptase Polymerase Chain Reaction, SMN Complex Proteins, Sequence Homology, Nucleic Acid, Survival of Motor Neuron 1 Protein, Survival of Motor Neuron 2 Protein, Transcription, Genetic, Transfection, Amino Acid Motifs

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          Abstract

          Alteration of correct splicing patterns by disruption of an exonic splicing enhancer may be a frequent mechanism by which point mutations cause genetic diseases. Spinal muscular atrophy results from the lack of functional survival of motor neuron 1 gene (SMN1), even though all affected individuals carry a nearly identical, normal SMN2 gene. SMN2 is only partially active because a translationally silent, single-nucleotide difference in exon 7 causes exon skipping. Using ESE motif-prediction tools, mutational analysis and in vivo and in vitro splicing assays, we show that this single-nucleotide change occurs within a heptamer motif of an exonic splicing enhancer, which in SMN1 is recognized directly by SF2/ASF. The abrogation of the SF2/ASF-dependent ESE is the basis for inefficient inclusion of exon 7 in SMN2, resulting in the spinal muscular atrophy phenotype.

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          Journal
          10.1038/ng854
          11925564

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