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Human Molecular Genetics Advance Access originally published online on February 9, 2005
Human Molecular Genetics 2005 14(6):845-857; doi:10.1093/hmg/ddi078
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Human Molecular Genetics, Vol. 14, No. 6 © Oxford University Press 2005; all rights reserved

SMN{Delta}7, 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

Thanh T. Le1, Lan T. Pham1, Matthew E.R. Butchbach1,{ddagger}, Honglai L. Zhang4,{ddagger}, Umrao R. Monani1,2,{dagger}, Daniel D. Coovert1, Tatiana O. Gavrilina1, Lei Xing4, Gary J. Bassell4 and Arthur H.M. Burghes1,2,3,*

1Department of Molecular and Cellular Biochemistry, 2Department of Neurology, College of Medicine and Public Health, 3Department of Molecular Genetics, College of Biological Sciences, Ohio State University, Columbus, OH, USA and 4Department of Neuroscience, Rose F. Kennedy Center for Mental Retardation, Albert Einstein College of Medicine, Bronx, NY, USA

* To whom correspondence should be addressed at: Department of Molecular and Cellular Biochemistry, 363 Hamilton Hall, 1645 Neil Avenue, Columbus, OH, 43210 USA. Tel: +1 6146884759; Fax: +1 6142924118; Email: burghes.1{at}osu.edu

Received October 29, 2004; Revised January 13, 2005; Accepted January 27, 2005

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 (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 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 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.

{dagger} Present address: Department of Neurology, Columbia University, New York, NY, USA.

{ddagger} These authors contributed equally to this manuscript.


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