title: Identification of a cis-acting element for the regulation of SMN exon 7 splicing.
abstract: Spinal muscular atrophy results from the loss of functional survival motor neuron (SMN1) alleles. Two nearly identical copies of SMN exist and differ only by a single non-polymorphic C to T transition in exon 7. This transition leads to alteration of exon 7 splicing; that is, SMN1 produces a full-length transcript, whereas SMN2 expresses a low level of full-length transcript and predominantly an isoform lacking exon 7. The truncated transcript of SMN encodes a less stable protein with reduced self-oligomerization activity that fails to compensate for the loss of SMN1. In this paper, we identified a cis-acting element (element 1), which is composed of 45 bp in intron 6 responsible for the regulation of SMN exon 7 splicing. Mutations in element 1 or treatment with antisense oligonucleotides directed toward element 1 caused an increase in exon 7 inclusion. An approximately 33-kDa protein was demonstrated to associate with a pre-mRNA sequence containing both element 1 and the C to T transition in SMN exon 7 but not with the sequence containing mutated element 1, suggesting that the binding of the approximately 33-kDa protein plays crucial roles in the skipping of SMN exon 7 containing the C to T transition.
authors.affiliation: Division of Structural Cellular Biology, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0101, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyajima
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Miyaso
authors.forename: Masayo
authors.initials: M
authors.lastname: Okumura
authors.forename: Junko
authors.initials: J
authors.lastname: Kurisu
authors.forename: Kazunori
authors.initials: K
authors.lastname: Imaizumi
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D019556:COS Cells; D017362:Cyclic AMP Response Element-Binding Protein; D005091:Exons; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012322:RNA Precursors / Q000378:metabolism; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins / Q000378:metabolism; D055532:SMN Complex Proteins; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D055532:SMN Complex Proteins; D015534:Trans-Activators