Journal Article

SMNΔ7, the major product of the centromeric survival motor neuron (<i>SMN2</i>) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN

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

in Human Molecular Genetics

Volume 14, issue 6, pages 845-857
Published in print March 2005 | ISSN: 0964-6906
Published online February 2005 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi078
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

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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 (SMNΔ7). SMNΔ7 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 SMNΔ7 in SMA, we created transgenic mice expressing SMNΔ7 and crossed them onto a severe SMA background. We found that the SMNΔ7 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 SMNΔ7 can associate with each other and we suggest that this association stabilizes SMNΔ7 protein turnover and ameliorates the SMA phenotype by increasing the amount of oligomeric SMN. The increased survival of the SMNΔ7 SMA mice we report will facilitate testing of therapies and indicates the importance of considering co-complexes of SMN and SMNΔ7 when analyzing SMN function.

Journal Article.  10809 words.  Illustrated.

Subjects: Genetics and Genomics

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