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 (∼80%), resulting in a highly unstable and almost undetectable protein (SMNΔ7). We show that this splicing defect creates a potent degradation signal (degron; SMNΔ7-DEG) at SMNΔ7's C-terminal 15 amino acids. The S270A mutation inactivates SMNΔ7-DEG, generating a stable SMNΔ7 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 SMNΔ7-DEG activity.