title: An intronic splicing enhancer element in survival motor neuron (SMN) pre-mRNA.
abstract: Spinal muscular atrophy is caused by the homozygous loss of survival motor neuron 1 (SMN1). SMN2, a nearly identical copy gene, differs from SMN1 only by a single nonpolymorphic C to T transition in exon 7, which leads to alteration of exon 7 splicing; SMN2 leads to exon 7 skipping and expression of a nonfunctional gene product and fails to compensate for the loss of SMN1. The exclusion of SMN exon 7 is critical for the onset of this disease. Regulation of SMN exon 7 splicing was determined by analyzing the roles of the cis-acting element in intron 7 (element 2), which we previously identified as a splicing enhancer element of SMN exon 7 containing the C to T transition. The minimum sequence essential for activation of the splicing was determined to be 24 nucleotides, and RNA structural analyses showed a stem-loop structure. Deletion of this element or disruption of the stem-loop structure resulted in a decrease in exon 7 inclusion. A gel shift assay using element 2 revealed formation of RNA-protein complexes, suggesting that the binding of the trans-acting proteins to element 2 plays a crucial role in the splicing of SMN exon 7 containing the C to T transition.
authors.affiliation: Division of Structural Cellular Biology, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0101, Japan.
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Miyaso
authors.forename: Masayo
authors.initials: M
authors.lastname: Okumura
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kondo
authors.forename: Satoshi
authors.initials: S
authors.lastname: Higashide
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyajima
authors.forename: Kazunori
authors.initials: K
authors.lastname: Imaizumi
mesh_terms: D000818:Animals; D019556:COS Cells; D017362:Cyclic AMP Response Element-Binding Protein; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D007438:Introns / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012322:RNA Precursors / Q000737:chemistry*; D012326:RNA Splicing / Q000235:genetics*; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins