title: A degron created by SMN2 exon 7 skipping is a principal contributor to spinal muscular atrophy severity.
abstract: Spinal muscular atrophy (SMA) is caused by homozygous survival of motor neurons 1 (SMN1) gene deletions, leaving a duplicate gene, SMN2, as the sole source of SMN protein. However, most of the mRNA produced from SMN2 pre-mRNA is exon 7-skipped ( approximately 80%), resulting in a highly unstable and almost undetectable protein (SMNDelta7). We show that this splicing defect creates a potent degradation signal (degron; SMNDelta7-DEG) at SMNDelta7's C-terminal 15 amino acids. The S270A mutation inactivates SMNDelta7-DEG, generating a stable SMNDelta7 that rescues viability of SMN-deleted cells. These findings explain a key aspect of the SMA disease mechanism, and suggest new treatment approaches based on interference with SMNDelta7-DEG activity.
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Sungchan
authors.initials: S
authors.lastname: Cho
authors.forename: Gideon
authors.initials: G
authors.lastname: Dreyfuss
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D005091:Exons / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D055550:Protein Stability; D016415:Sequence Alignment; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein