title: Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1.
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.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Cartegni
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Krainer
mesh_terms: D020816:Amino Acid Motifs; D001483:Base Sequence; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein; D004252:DNA Mutational Analysis; D005091:Exons; D006801:Humans; D007438:Introns; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation; D014176:Protein Biosynthesis; D012313:RNA / Q000378:metabolism; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055532:SMN Complex Proteins; D012689:Sequence Homology, Nucleic Acid; D000068103:Serine-Arginine Splicing Factors; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D014158:Transcription, Genetic; D014162:Transfection; D014466:Ultraviolet Rays
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D000068103:Serine-Arginine Splicing Factors; D012313:RNA