SMNΔ7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN
doi: 10.1093/hmg/ddi078
pmid: 15703193
SMNΔ7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN
Spinal muscular atrophy (SMA) is an autosomal recessive disorder in humans which results in the loss of motor neurons. It is caused by reduced levels of the survival motor neuron (SMN) protein as a result of loss or mutation of the SMN1 gene. SMN is encoded by two genes, SMN1 and SMN2, which essentially differ by a single nucleotide in exon 7. As a result, the majority of the transcript from SMN2 lacks exon 7 (SMNDelta7). SMNDelta7 may be toxic and detrimental in SMA, which, if true, could lead to adverse effects with drugs that stimulate expression of SMN2. To determine the role of SMNDelta7 in SMA, we created transgenic mice expressing SMNDelta7 and crossed them onto a severe SMA background. We found that the SMNDelta7 is not detrimental in that it extends survival of SMA mice from 5.2 to 13.3 days. Unlike mice with selective deletion of SMN exon 7 in muscle, these mice with a small amount of full-length SMN (FL-SMN) did not show a dystrophic phenotype. This indicates that low levels of FL-SMN as found in SMA patients and absence of FL-SMN in muscle tissue have different effects and raises the question of the importance of high SMN levels in muscle in the presentation of SMA. SMN and SMNDelta7 can associate with each other and we suggest that this association stabilizes SMNDelta7 protein turnover and ameliorates the SMA phenotype by increasing the amount of oligomeric SMN. The increased survival of the SMNDelta7 SMA mice we report will facilitate testing of therapies and indicates the importance of considering co-complexes of SMN and SMNDelta7 when analyzing SMN function.
- The Ohio State University United States
- Albert Einstein College of Medicine United States
- University of Minnesota United States
RNA-Binding Proteins, Mice, Transgenic, Nerve Tissue Proteins, SMN Complex Proteins, Exons, Survival of Motor Neuron 1 Protein, Muscular Atrophy, Spinal, Survival of Motor Neuron 2 Protein, Mice, Gene Expression Regulation, Animals, Humans, Cyclic AMP Response Element-Binding Protein, Protein Binding
RNA-Binding Proteins, Mice, Transgenic, Nerve Tissue Proteins, SMN Complex Proteins, Exons, Survival of Motor Neuron 1 Protein, Muscular Atrophy, Spinal, Survival of Motor Neuron 2 Protein, Mice, Gene Expression Regulation, Animals, Humans, Cyclic AMP Response Element-Binding Protein, Protein Binding
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