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Published 6 January 2003. doi:10.1083/jcb.200208079
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© The Rockefeller University Press, 0021-9525/2003/1/41 $5.00
The Journal of Cell Biology, Volume 160, Number 1, 41-52

Article

A transgene carrying an A2G missense mutation in the SMN gene modulates phenotypic severity in mice with severe (type I) spinal muscular atrophy



Umrao R. Monani1, Matthew T. Pastore2, Tatiana O. Gavrilina1, Sibylle Jablonka5, Thanh T. Le2, Catia Andreassi1, Jennifer M. DiCocco2, Christian Lorson6, Elliot J. Androphy7, Michael Sendtner5, Michael Podell3 and Arthur H.M. Burghes1,2,4

1 Departments of Neurology, Ohio State University, Columbus, OH 43210
2 Molecular and Cellular Biochemistry, Ohio State University, Columbus, OH 43210
3 Veterinary Clinical Sciences, Ohio State University, Columbus, OH 43210
4 Molecular Genetics, Ohio State University, Columbus, OH 43210
5 Institute of Clinical Neurobiology, University of Würzburg, D-97080 Würzburg, Germany
6 Department of Biology, Arizona State University, Tempe, AZ 85287
7 Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605

Address correspondence to Umrao R. Monani, Department of Molecular and Cellular Biochemistry, 363 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210. Tel.: (614) 688-4759. Fax: (614) 292-4118. E-mail: monani.2{at}osu.edu; or Arthur H.M. Burghes, Department of Molecular and Cellular Biochemistry, 363 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210. Tel.: (614) 688-4759. Fax: (614) 292-4118. E-mail: burghes.1{at}osu.edu

5q spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and the leading genetic cause of infantile death. Patients lack a functional survival of motor neurons (SMN1) gene, but carry one or more copies of the highly homologous SMN2 gene. A homozygous knockout of the single murine Smn gene is embryonic lethal. Here we report that in the absence of the SMN2 gene, a mutant SMN A2G transgene is unable to rescue the embryonic lethality. In its presence, the A2G transgene delays the onset of motor neuron loss, resulting in mice with mild SMA. We suggest that only in the presence of low levels of full-length SMN is the A2G transgene able to form partially functional higher order SMN complexes essential for its functions. Mild SMA mice exhibit motor neuron degeneration, muscle atrophy, and abnormal EMGs. Animals homozygous for the mutant transgene are less severely affected than heterozygotes. This demonstrates the importance of SMN levels in SMA even if the protein is expressed from a mutant allele. Our mild SMA mice will be useful in (a) determining the effect of missense mutations in vivo and in motor neurons and (b) testing potential therapies in SMA.

Key Words: SMA; SMN; mouse model; motor neurons; transgene


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