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Human Molecular Genetics Advance Access published online on February 9, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi078
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© The Author 2005. Published by Oxford University Press. All rights reserved

Article

SMN{Delta}7, the major product of the centromeric survival motor neuron gene (SMN2), extends survival in mice with spinal muscular atrophy and associates with full-length SMN

Thanh T. Le 1, Lan T. Pham 1, Matthew E.R. Butchbach 1, Honglai L. Zhang 2, Umrao R. Monani 3, Daniel D. Coovert 1, Tatiana O. Gavrilina 1, Lei Xing 2, Gary J. Bassell 2, and Arthur H.M. Burghes 4*

1 Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio USA
2 Department of Neuroscience Rose F. Kennedy Center for Mental Retardation, Albert Einstein College of Medicine, Bronx, New York USA
3 Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio USA; Department of Neurology, College of Medicine and Public Health, Ohio State University, Columbus, Ohio USA
4 Dept of Molecular and Cellular Biochemistry, 363 Hamilton Hall, 1645 Neil Ave, Columbus OH USA 43210; Department of Neurology, College of Medicine and Public Health, Ohio State University, Columbus, Ohio USA; Department of Molecular Genetics, College of Biological Sciences, Ohio State University, Columbus, Ohio USA

* To whom correspondence should be addressed.
Arthur H.M. Burghes, E-mail: burghes.1{at}osu.edu


  Abstract

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 protein (SMN) 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 (SMN{Delta}7). SMN{Delta}7 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 SMN{Delta}7 in SMA, we created transgenic mice expressing SMN{Delta}7 and crossed them onto a severe SMA background. We found that the SMN{Delta}7 is not detrimental in that it extends survival of SMA mice from 5.2 days 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 did not show a dystrophic phenotype. This indicates that low levels of full length SMN as found in SMA patients and absence of full length 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 SMN{Delta}7 can associate with each other and we suggest that this association stabilizes SMN{Delta}7 protein turnover and ameliorates the SMA phenotype by increasing the amount of oligomeric SMN. The increased survival of the SMN{Delta}7 SMA mice we report will facilitate testing of therapies and indicates the importance of considering co-complexes of SMN and SMN{Delta}7 when analyzing SMN function.


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