Journal
GENES & DEVELOPMENT
Volume 24, Issue 5, Pages 438-442Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1884910
Keywords
Survival of motor neurons (SMN); spinal muscular atrophy (SMA); motor neuron degenerative disease; protein degradation signal (degron); protein stability; pre-mRNA splicing
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Funding
- Association Francxaise Contre les Myopathies (AFM)
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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 (similar to 80%), resulting in a highly unstable and almost undetectable protein (SMN Delta 7). We show that this splicing defect creates a potent degradation signal (degron; SMN Delta 7-DEG) at SMN Delta 7's C-terminal 15 amino acids. The S270A mutation inactivates SMN Delta 7-DEG, generating a stable SMN Delta 7 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 SMN Delta 7-DEG activity.
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