A degron created by SMN2 exon 7 skipping is a principal contributor to spinal muscular atrophy severity
- Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
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.
Keywords
- Survival of motor neurons (SMN)
- spinal muscular atrophy (SMA)
- motor neuron degenerative disease
- protein degradation signal (degron)
- protein stability
- pre-mRNA splicing
Footnotes
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↵1 Corresponding author.
E-MAIL gdreyfuss{at}hhmi.upenn.edu; FAX (215) 573-2000.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1884910.
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Supplemental material is available at http://www.genesdev.org.
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- Received November 11, 2009.
- Accepted January 13, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press
