A transgene carrying an A2G missense mutation in the SMN gene modulates phenotypic severity in mice with severe (type I) spinal muscular atrophy.
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.
Monani
Umrao R
UR
Department of Neurology, Ohio State University, Columbus, OH 43210, USA. monani.2@osu.edu
Pastore
Matthew T
MT
Gavrilina
Tatiana O
TO
Jablonka
Sibylle
S
Le
Thanh T
TT
Andreassi
Catia
C
DiCocco
Jennifer M
JM
Lorson
Christian
C
Androphy
Elliot J
EJ
Sendtner
Michael
M
Podell
Michael
M
Burghes
Arthur H M
AH
D000818:Animals; D001369:Axons / Q000378:metabolism; D015139:Blotting, Southern; D015153:Blotting, Western; D017362:Cyclic AMP Response Element-Binding Protein; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004576:Electromyography; D004594:Electrophysiology; D005838:Genotype; D005982:Glutathione Transferase / Q000378:metabolism; D006720:Homozygote; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D009046:Motor Neurons / Q000473:pathology; D009132:Muscles / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D011485:Protein Binding; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055532:SMN Complex Proteins; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D013997:Time Factors; D014018:Tissue Distribution; D019076:Transgenes
D017362:Cyclic AMP Response Element-Binding Protein; D018076:DNA, Complementary; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D005982:Glutathione Transferase