title: Intron 7 conserved sequence elements regulate the splicing of the SMN genes.
abstract: Proximal spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of the survival motor neuron (SMN) protein. In humans there are two nearly identical SMN genes, SMN1 and SMN2. The SMN2 gene generates a truncated protein, due to a C to T nucleotide alteration in exon 7, which leads to inefficient RNA splicing of exon 7. This exclusion of SMN exon 7 is central to the onset of the SMA disease. Exon 7 splicing is regulated by a number of exonic and intronic splicing regulatory sequences and the trans-factors that bind them. Here, we identify conserved intronic sequences in the SMN genes. Five regions were examined due to conservation and their proximity to exons 6 through 8. Using mutagenesis two conserved elements located in intron 7 of the SMN genes that affect exon 7 splicing have been identified. Additional analysis of one of these regions showed decreased inclusion of exon 7 in SMN transcripts when deletions or mutations were introduced. Furthermore, multimerization of this conserved region was capable of restoring correct SMN splicing. Together these results describe a novel intronic splicing enhancer sequence located in the final intron of the SMN genes. This discovery provides insight into the splicing of the SMN genes using conserved intonic sequence as a tool to uncover regions of importance in pre-messenger RNA splicing. A better understanding of the way SMN premRNA is spliced can lead to the development of new therapies.
authors.affiliation: The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA. Jordan.Gladman@nationwidechildrens.org
authors.forename: Jordan T
authors.initials: JT
authors.lastname: Gladman
authors.forename: Dawn S
authors.initials: DS
authors.lastname: Chandler
mesh_terms: D001483:Base Sequence; D002478:Cells, Cultured; D017124:Conserved Sequence / Q000235:genetics*; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D012326:RNA Splicing; D055532:SMN Complex Proteins / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: D055532:SMN Complex Proteins
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