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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Motifs
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Base Sequence
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Cell Line
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Cyclic AMP Response Element-Binding Protein
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DNA Mutational Analysis
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Exons*
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Humans
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Introns
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Models, Genetic
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Molecular Sequence Data
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Muscular Atrophy, Spinal / genetics*
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Mutagenesis, Site-Directed
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Mutation
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Nerve Tissue Proteins / chemistry
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Nerve Tissue Proteins / genetics*
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Nuclear Proteins / chemistry
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Nuclear Proteins / genetics*
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Phenotype
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Point Mutation
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Protein Biosynthesis
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RNA / metabolism
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RNA Splicing*
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RNA, Messenger / metabolism
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RNA-Binding Proteins
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Reverse Transcriptase Polymerase Chain Reaction
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SMN Complex Proteins
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Sequence Homology, Nucleic Acid
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Serine-Arginine Splicing Factors
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Survival of Motor Neuron 1 Protein
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Survival of Motor Neuron 2 Protein
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Transcription, Genetic
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Transfection
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Ultraviolet Rays
Substances
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Cyclic AMP Response Element-Binding Protein
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Nerve Tissue Proteins
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Nuclear Proteins
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RNA, Messenger
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RNA-Binding Proteins
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SMN Complex Proteins
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SMN1 protein, human
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SMN2 protein, human
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Survival of Motor Neuron 1 Protein
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Survival of Motor Neuron 2 Protein
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Serine-Arginine Splicing Factors
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RNA