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. Monani, Matthew T. Pastore, Tatiana O. Gavrilina, Sibylle Jablonka, Thanh T. Le, Catia Andreassi, Jennifer M. DiCocco, Christian Lorson, Elliot Androphy, Michael Sendtner, Michael Podell, Arthur H M Burghes

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)41-52
Number of pages12
JournalJournal of Cell Biology
Volume160
Issue number1
DOIs
StatePublished - Jan 6 2003
Externally publishedYes

Fingerprint

Spinal Muscular Atrophies of Childhood
Spinal Muscular Atrophy
Missense Mutation
Transgenes
Motor Neurons
Genes
SMN Complex Proteins
Nerve Degeneration
Muscular Atrophy
Medical Genetics
Heterozygote
Cause of Death
Alleles

Keywords

  • Motor neurons
  • Mouse model
  • SMA
  • SMN
  • Transgene

ASJC Scopus subject areas

  • Cell Biology

Cite this

Monani, U. R., Pastore, M. T., Gavrilina, T. O., Jablonka, S., Le, T. T., Andreassi, C., ... Burghes, A. H. M. (2003). A transgene carrying an A2G missense mutation in the SMN gene modulates phenotypic severity in mice with severe (type I) spinal muscular atrophy. Journal of Cell Biology, 160(1), 41-52. https://doi.org/10.1083/jcb.200208079

A transgene carrying an A2G missense mutation in the SMN gene modulates phenotypic severity in mice with severe (type I) spinal muscular atrophy. / Monani, Umrao R.; Pastore, Matthew T.; Gavrilina, Tatiana O.; Jablonka, Sibylle; Le, Thanh T.; Andreassi, Catia; DiCocco, Jennifer M.; Lorson, Christian; Androphy, Elliot; Sendtner, Michael; Podell, Michael; Burghes, Arthur H M.

In: Journal of Cell Biology, Vol. 160, No. 1, 06.01.2003, p. 41-52.

Research output: Contribution to journalArticle

Monani, UR, Pastore, MT, Gavrilina, TO, Jablonka, S, Le, TT, Andreassi, C, DiCocco, JM, Lorson, C, Androphy, E, Sendtner, M, Podell, M & Burghes, AHM 2003, 'A transgene carrying an A2G missense mutation in the SMN gene modulates phenotypic severity in mice with severe (type I) spinal muscular atrophy', Journal of Cell Biology, vol. 160, no. 1, pp. 41-52. https://doi.org/10.1083/jcb.200208079
Monani, Umrao R. ; Pastore, Matthew T. ; Gavrilina, Tatiana O. ; Jablonka, Sibylle ; Le, Thanh T. ; Andreassi, Catia ; DiCocco, Jennifer M. ; Lorson, Christian ; Androphy, Elliot ; Sendtner, Michael ; Podell, Michael ; Burghes, Arthur H M. / A transgene carrying an A2G missense mutation in the SMN gene modulates phenotypic severity in mice with severe (type I) spinal muscular atrophy. In: Journal of Cell Biology. 2003 ; Vol. 160, No. 1. pp. 41-52.
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