B6;129-Gaa^tm1Rabn/J

Stock number: 004154
Product name: 6^neo, PD
Research areas: Metabolism Research, Mouse/Human Gene Homologs

Description

These Gaa knock-out mice, commonly called 6^neo or PD mice, exhibit a progressive accumulation of lysosomal glycogen in heart and skeletal muscle, and diaphragm with reduced mobility and progressive muscle weakness that is associated with Pompe disease.

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Detailed description

Pompe disease is an inherited disorder caused by a deficiency of alpha glucosidase, encoded by the GAA gene. Lysosomal glycogen accumulates in tissues, including muscles (most notably skeletal and cardiac) and the central nervous system.

Exon 6 of the mouse Gaa (glucosidase, alpha, acid) gene was targeted with a stop codon and neomycin cassette, and flanked by loxP sites to create this 6^neo (or PD) knock-out allele. Low levels of transcript are detectable, but functional protein is absent.

At birth, mice that are homozygotes are viable, normal in size, and do not display any gross physical or behavioral abnormalities. By 3 weeks of age, light microscopy (PAS staining) reveals a progressive accumulation of lysosomal glycogen in heart and skeletal muscle, and the 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 are 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-Gaa^tm1Jhng/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.

Development

Exon 6 of the mouse Gaa (glucosidase, alpha, acid) gene was targeted with a termination codon and a neomycin cassette and flanked by loxP sites via homologous recombination in 129X1/SvJ-derived RW-4 embryonic stem (ES) cells to create this 6^neo (or PD) knock-out allele. Resulting chimeric males were bred with wild-type C57BL/6J females. This strain was maintained on a mixed C57BL/6J-129X1/SvJ genetic background by the donating laboratory.

Allele

Symbol: Gaa^tm1Rabn
Name: targeted mutation 1, Nina Raben
MGI accession ID: MGI:2148550
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Gaa
Marker name: glucosidase, alpha, acid
Chromosome: 11
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.