These Gaa knock-out mice exhibit a progressive accumulation of lysosomal glycogen in heart and skeletal muscle, and diaphragm with reduced mobility and progressive muscle weakness.
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Nina Raben, NIAMS, NIH
At birth, mice that are homozygous for the targeted allele are viable, normal in size and do not display any gross physical or behavioral abnormalities. Low levels of transcript are detectable, but functional protein is absent. By 3 weeks of age, light microscopy (PAS staining) reveals a progressive accumulation of lysosomal glycogen in heart and skeletal muscle, and diaphragm. Concomitant with accumulating glycogen is a significant reduction in the number of myofibrils and signs of damaged muscle structure. Reduced mobility and progressive muscle weakness is observed by 3-4 weeks of age. By 8-9 months of age, muscle glycogen storage and progressive muscle weakness are obvious but do not become clinically evident until 12 months of age, delaying clinical assessment of treatment efficacy. Adults are fertile. These mice recapitulate key features of glycogen storage disease type II (GSDII) and provide a model for studying the underlying mechanism of GSDII.
Of note, C57BL/6NJ-Gaatm1Jhng/J mice, available as Stock No. 034609, also survive into adulthood, however they carry a mutation orthologous to one found in human IOPD making it much “closer” in genetic homology to human Pompe Disease.
A targeting vector containing Gaa sequence, neomycin resistance and herpes simplex virus thymidine kinase genes was utilized to disrupt exon 6. A stop codon and neomycin resistance gene were introduced to exon 6 which was flanked by loxP sites. The construct was electroporated into 129X1/SvJ-derived RW-4 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. Resulting chimeric male animals were mated to wild-type C57BL/6J mice.
|Allele Name||targeted mutation 1, Nina Raben|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||6neo; Gaa-|
|Gene Symbol and Name||Gaa, glucosidase, alpha, acid|
|Strain of Origin||129X1/SvJ|
|Molecular Note||Insertion of a neomycin cassette into floxed exon 6. No transcript derived from this gene was detected in skeletal muscle of homozygous mice by RT-PCR analysis, and no encoded protein was detected by Western blot in liver extracts from homozygous mice.|
|Mutations Made By|| |
Nina Raben, NIAMS, NIH
Heterozygotes and homozygotes are viable and fertile.
When using the 6neo mouse strain in a publication, please cite the originating article(s) and include JAX stock #004154 in your Materials and Methods section.