title: A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy.
abstract: SMN1 and SMN2 (survival motor neuron) encode identical proteins. A critical question is why only the homozygous loss of SMN1, and not SMN2, results in spinal muscular atrophy (SMA). Analysis of transcripts from SMN1/SMN2 hybrid genes and a new SMN1 mutation showed a direct relationship between presence of disease and exon 7 skipping. We have reported previously that the exon-skipped product SMNDelta7 is partially defective for self-association and SMN self-oligomerization correlated with clinical severity. To evaluate systematically which of the five nucleotides that differ between SMN1 and SMN2 effect alternative splicing of exon 7, a series of SMN minigenes was engineered and transfected into cultured cells, and their transcripts were characterized. Of these nucleotide differences, the exon 7 C-to-T transition at codon 280, a translationally silent variance, was necessary and sufficient to dictate exon 7 alternative splicing. Thus, the failure of SMN2 to fully compensate for SMN1 and protect from SMA is due to a nucleotide exchange (C/T) that attenuates activity of an exonic enhancer. These findings demonstrate the molecular genetic basis for the nature and pathogenesis of SMA and illustrate a novel disease mechanism. Because individuals with SMA retain the SMN2 allele, therapy targeted at preventing exon 7 skipping could modify clinical outcome.
authors.affiliation: Department of Dermatology, New England Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Lorson
authors.forename: E
authors.initials: E
authors.lastname: Hahnen
authors.forename: E J
authors.initials: EJ
authors.lastname: Androphy
authors.forename: B
authors.initials: B
authors.lastname: Wirth
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D017362:Cyclic AMP Response Element-Binding Protein; D005091:Exons; D005347:Fibroblasts / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D017354:Point Mutation; D014176:Protein Biosynthesis; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055532:SMN Complex Proteins; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D014158:Transcription, Genetic
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; 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