Characterization of behavioral and neuromuscular junction phenotypes in a novel allelic series of SMA mouse models.
A number of mouse models for spinal muscular atrophy (SMA) have been genetically engineered to recapitulate the severity of human SMA by using a targeted null mutation at the mouse Smn1 locus coupled with the transgenic addition of varying copy numbers of human SMN2 genes. Although this approach has been useful in modeling severe SMA and very mild SMA, a mouse model of the intermediate form of the disease would provide an additional research tool amenable for drug discovery. In addition, many of the previously engineered SMA strains are multi-allelic by design, containing a combination of transgenes and targeted mutations in the homozygous state, making further genetic manipulation difficult. A new genetic engineering approach was developed whereby variable numbers of SMN2 sequences were incorporated directly into the murine Smn1 locus. Using combinations of these alleles, we generated an allelic series of SMA mouse strains harboring no, one, two, three, four, five, six or eight copies of SMN2. We report here the characterization of SMA mutants in this series that displayed a range in disease severity from embryonic lethal to viable with mild neuromuscular deficits.
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Melissa
M
Osborne
Daniel
D
Gomez
Zhihua
Z
Feng
Corissa
C
McEwen
Jose
J
Beltran
Kim
K
Cirillo
Bassem
B
El-Khodor
Ming-Yi
MY
Lin
Yun
Y
Li
Wendy M
WM
Knowlton
David D
DD
McKemy
Laurent
L
Bogdanik
Katherine
K
Butts-Dehm
Kimberly
K
Martens
Crystal
C
Davis
Rosalinda
R
Doty
Keegan
K
Wardwell
Afshin
A
Ghavami
Dione
D
Kobayashi
Chien-Ping
CP
Ko
Sylvie
S
Ramboz
Cathleen
C
Lutz
D000483:Alleles; D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D005838:Genotype; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D009469:Neuromuscular Junction / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics / Q000378:metabolism
C526477:SMN2 protein, human; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein