title: Premature termination mutations in exon 3 of the SMN1 gene are associated with exon skipping and a relatively mild SMA phenotype.
abstract: Autosomal recessive spinal muscular atrophy (SMA) is a common motor neuron disease caused by absence or mutation in the survival motor neuron (SMN1) gene. SNM1 and a nearly identical copy, SMN2, encode identical proteins, but SMN2 only produces a little full length protein due to alternative splicing. The level of functional SMN protein and the number of SMN2 genes correlate with the clinical phenotype ranging from severe to very mild. Here, we report on premature termination mutations in SMN1 exon 3 (425del5 and W102X) which induce skipping of the mutated exon. The novel nonsense mutation W102X was detected in two patients with a relatively mild phenotype who had only two copies of the SMN2 gene, a number that has previously been found associated with the severe form of SMA. We show that the shortened transcripts are translated into predicted in frame protein isoforms. Aminoglycoside treatment suppressed the nonsense mutation in cultured cells and abolished exon skipping. Fibroblasts from both patients show a high number of nuclear structures containing SMN protein (gems). These findings suggest that the protein isoform lacking the exon 3 encoded region contributes to the formation of the nuclear protein complex which may account for the milder clinical phenotype.
authors: Institute of Medical Genetics, Catholic University, Rome, Italy.
authors: V
authors: V
authors: Sossi
authors: A
authors: A
authors: Giuli
authors: T
authors: T
authors: Vitali
authors: F
authors: F
authors: Tiziano
authors: M
authors: M
authors: Mirabella
authors: A
authors: A
authors: Antonelli
authors: G
authors: G
authors: Neri
authors: C
authors: C
authors: Brahe
mesh_terms: D000328:Adult; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D015139:Blotting, Southern; D015153:Blotting, Western; D002675:Child, Preschool; D003001:Cloning, Molecular; D017362:Cyclic AMP Response Element-Binding Protein; D017931:DNA Primers / Q000737:chemistry; D005091:Exons; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055532:SMN Complex Proteins; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D017362:Cyclic AMP Response Element-Binding Protein; D017931:DNA Primers; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; 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