A degron created by SMN2 exon 7 skipping is a principal contributor to spinal muscular atrophy severity

作者：Cho Sungchan; Dreyfuss Gideon^*

来源：Genes & Development, 2010, 24(5): 438-442.

DOI：10.1101/gad.1884910

• Survival of motor neurons (SMN)
• spinal muscular atrophy (SMA)
• motor neuron degenerative disease
• protein degradation signal (degron)
• protein stability
• pre-mRNA splicing

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.

• 出版日期2010-3-1