Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse   Donating Investigator Nina Raben,   NIAMS, NIH

Description
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 wasting and weakness are obvious. 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.

Development
A targeting vector containing Gaa sequence, neomycin resistance and herpes simplex virus thymidine kinase genes was utilized to disrupt exon 6. A stop codon was introduced into exon 6 upstream of the inserted neomycin resistance gene and similarly oriented loxP sites were placed in Gaa introns 5 and 6, flanking the neomycin resistance gene. 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.

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Glycogen Storage Disease II

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Gaa^tm1Rabn/Gaa^tm1Rabn

        involves: 129X1/SvJ * C57BL/6

• behavior/neurological phenotype
• abnormal gait   (MGI Ref ID J:76435)
  • at 7-9 months of age, display a weak, waddling gait   (MGI Ref ID J:48839)
• decreased grip strength
  • in the wire-hang task, homozygous mutants perform poorly, indicating poor muscular function and grip strength   (MGI Ref ID J:48839)
  • at 15-16 weeks of age, homozygous mutant mice are almost never able to hold on to the inverted screen for more than 2 minutes   (MGI Ref ID J:48839)
• decreased vertical activity
  • starting at 3.5 weeks of age, display a striking reduction in vertical activity in the open field   (MGI Ref ID J:48839)
• hindlimb paralysis
  • by 16-18 months of age, display near paralysis of the hindlimbs and an abnormal footprint pathway   (MGI Ref ID J:76435)
• hypoactivity
  • as early as 3.5 weeks of age, display reduced activity in the horizontal open field test, and consistently perform significantly worse than age-matched heterozygotes when placed in an open field environment   (MGI Ref ID J:48839)
  • develop abnormal field behavior within the first months of life   (MGI Ref ID J:76435)
• impaired coordination
  • severely impaired on a rotarod at 8-11 months of age   (MGI Ref ID J:76435)
• muscle phenotype
• abnormal muscle fiber morphology
  • display a significant reduction in the number of myofibrils and lack of lateral myofibrillar registration   (MGI Ref ID J:48839)
• • abnormal sarcomere morphology
    • signs of sarcomere degradation   (MGI Ref ID J:48839)
  • • abnormal Z lines
      • deformation of Z lines   (MGI Ref ID J:48839)
• cardiomyopathy   (MGI Ref ID J:48839)
• increased skeletal muscle glycogen level
  • accumulation of lysosomal glycogen in skeletal muscle   (MGI Ref ID J:48839)
  • in contrast to frozen quadricep muscles from wild-type mice which contain very little glycogen and >50% of their glycogen phosphorylase is in the form of phosphorylase-a (Ph-a), quadricep muscles from homozygous mutant mice have little or no Ph-a activity and contain 20 times or more glycogen   (MGI Ref ID J:73924)
  • massive accumulation of glycogen in skeletal muscle and diaphragm   (MGI Ref ID J:76435)
• muscle weakness
  • seen in older mice (8-9 months)   (MGI Ref ID J:48839)
• • progressive muscle weakness   (MGI Ref ID J:76435)
    • at 7-9 months of age, homozygotes show obvious signs of muscle weakness and muscle wasting   (MGI Ref ID J:48839)
    • by 16-18 months, homozygotes exhibit a severe lower back muscle wasting and anterior muscle wasting   (MGI Ref ID J:48839)
• myopathy
  • develop a progressive muscle wasting disorder with clinical features of glycogen storage disease II; average age of onset is 7.1 months for females and 8.1 months for males   (MGI Ref ID J:76435)
• cardiovascular system phenotype
• cardiomyopathy   (MGI Ref ID J:48839)
• cellular phenotype
• abnormal lysosome morphology
  • at >3 weeks of age, cardiac and skeletal muscle lysosomes increase in size and number, and display increased density of accumulated glycogen particles   (MGI Ref ID J:48839)
  • at >3 weeks of age, some cardiac and skeletal muscle lysosomes appear broken, suggesting that leakage of lysosomal proteases may contribute to the damage of muscle structure   (MGI Ref ID J:48839)
• homeostasis/metabolism phenotype
• increased glycogen level
  • massive accumulation of glycogen in heart and brain   (MGI Ref ID J:76435)
  • accumulation of lysosomal glycogen in the heart   (MGI Ref ID J:48839)
• • increased skeletal muscle glycogen level
    • accumulation of lysosomal glycogen in skeletal muscle   (MGI Ref ID J:48839)
    • in contrast to frozen quadricep muscles from wild-type mice which contain very little glycogen and >50% of their glycogen phosphorylase is in the form of phosphorylase-a (Ph-a), quadricep muscles from homozygous mutant mice have little or no Ph-a activity and contain 20 times or more glycogen   (MGI Ref ID J:73924)
    • massive accumulation of glycogen in skeletal muscle and diaphragm   (MGI Ref ID J:76435)
• skeleton phenotype
• kyphosis
  • by 16-18 months, homozygous mutant mice exhibit a striking kyphosis   (MGI Ref ID J:76435)

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Gaa^tm1Rabn related

Metabolism Research

Mouse/Human Gene Homologs
glycogen storage disease type II (GSDII)

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Gaatm1Rabn
Allele Name		targeted mutation 1, Nina Raben
Allele Type		Targeted (knock-out)
Common Name(s)		6neo; Gaa-;
Mutation Made By		Nina Raben,   NIAMS, NIH
Strain of Origin		129X1/SvJ
ES Cell Line Name		RW-4
ES Cell Line Strain		129X1/SvJ
Gene Symbol and Name		Gaa, glucosidase, alpha, acid
Chromosome		11
Gene Common Name(s)		E430018M07Rik; LYAG; RIKEN cDNA E430018M07 gene;
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. [MGI Ref ID J:48839]

Genotyping

Genotyping Information

Genotyping Protocols

Gaa^tm1Rabn, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Raben N; Nagaraju K; Lee E; Kessler P; Byrne B; Lee L; LaMarca M; King C; Ward J; Sauer B; Plotz P. 1998. Targeted disruption of the acid alpha-glucosidase gene in mice causes an illness with critical features of both infantile and adult human glycogen storage disease type II. J Biol Chem 273(30):19086-92. [PubMed: 9668092]  [MGI Ref ID J:48839]

Additional References

Raben N; Nagaraju K; Lee A; Lu N; Rivera Y; Jatkar T; Hopwood JJ; Plotz PH. 2003. Induction of tolerance to a recombinant human enzyme, acid alpha-glucosidase, in enzyme deficient knockout mice. Transgenic Res 12(2):171-8. [PubMed: 12739885]  [MGI Ref ID J:82912]

Raben N; Nagaraju K; Lee E; Plotz P. 2000. Modulation of disease severity in mice with targeted disruption of the acid alpha-glucosidase gene. Neuromuscul Disord 10(4-5):283-91. [PubMed: 10838256]  [MGI Ref ID J:76435]

Gaa^tm1Rabn related

Ashe KM; Taylor KM; Chu Q; Meyers E; Ellis A; Jingozyan V; Klinger K; Finn PF; Cooper CG; Chuang WL; Marshall J; McPherson JM; Mattaliano RJ; Cheng SH; Scheule RK; Moreland RJ. 2010. Inhibition of glycogen biosynthesis via mTORC1 suppression as an adjunct therapy for Pompe disease. Mol Genet Metab 100(4):309-15. [PubMed: 20554235]  [MGI Ref ID J:162416]

Douillard-Guilloux G; Raben N; Takikita S; Ferry A; Vignaud A; Guillet-Deniau I; Favier M; Thurberg BL; Roach PJ; Caillaud C; Richard E. 2009. Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease. Hum Mol Genet :. [PubMed: 19959526]  [MGI Ref ID J:155876]

Geel TM; McLaughlin PM; de Leij LF; Ruiters MH; Niezen-Koning KE. 2007. Pompe disease: Current state of treatment modalities and animal models. Mol Genet Metab 92(4):299-307. [PubMed: 17826266]  [MGI Ref ID J:128387]

Hawes ML; Kennedy W; O'callaghan MW; Thurberg BL. 2007. Differential muscular glycogen clearance after enzyme replacement therapy in a mouse model of Pompe disease. Mol Genet Metab 91(4):343-51. [PubMed: 17572127]  [MGI Ref ID J:123038]

Joseph A; Munroe K; Housman M; Garman R; Richards S. 2008. Immune tolerance induction to enzyme-replacement therapy by co-administration of short-term, low-dose methotrexate in a murine Pompe disease model. Clin Exp Immunol 152(1):138-46. [PubMed: 18307520]  [MGI Ref ID J:133581]

Khanna R; Flanagan JJ; Feng J; Soska R; Frascella M; Pellegrino LJ; Lun Y; Guillen D; Lockhart DJ; Valenzano KJ. 2012. The pharmacological chaperone AT2220 increases recombinant human acid alpha-glucosidase uptake and glycogen reduction in a mouse model of Pompe disease. PLoS One 7(7):e40776. [PubMed: 22815812]  [MGI Ref ID J:189616]

Koeberl DD; Li S; Dai J; Thurberg BL; Bali D; Kishnani PS. 2012. beta2 Agonists enhance the efficacy of simultaneous enzyme replacement therapy in murine Pompe disease. Mol Genet Metab 105(2):221-7. [PubMed: 22154081]  [MGI Ref ID J:180309]

Koeberl DD; Luo X; Sun B; McVie-Wylie A; Dai J; Li S; Banugaria SG; Chen YT; Bali DS. 2011. Enhanced efficacy of enzyme replacement therapy in Pompe disease through mannose-6-phosphate receptor expression in skeletal muscle. Mol Genet Metab 103(2):107-12. [PubMed: 21397538]  [MGI Ref ID J:172080]

Matalon R; Surendran S; Campbell GA; Michals-Matalon K; Tyring SK; Grady J; Cheng S; Kaye E. 2006. Hyaluronidase increases the biodistribution of acid alpha-1,4 glucosidase in the muscle of Pompe disease mice: an approach to enhance the efficacy of enzyme replacement therapy. Biochem Biophys Res Commun 350(3):783-7. [PubMed: 17027913]  [MGI Ref ID J:114503]

Mori J; Ishihara Y; Matsuo K; Nakajima H; Terada N; Kosaka K; Kizaki Z; Sugimoto T. 2008. Hematopoietic contribution to skeletal muscle regeneration in acid alpha-glucosidase knockout mice. J Histochem Cytochem 56(9):811-7. [PubMed: 18505932]  [MGI Ref ID J:141812]

Nayak S; Sivakumar R; Cao O; Daniell H; Byrne BJ; Herzog RW. 2012. Mapping the T helper cell response to acid alpha-glucosidase in Pompe mice. Mol Genet Metab 106(2):189-95. [PubMed: 22494547]  [MGI Ref ID J:184129]

Raben N; Danon M; Lu N; Lee E; Shliselfeld L; Skurat AV; Roach PJ; Lawrence JC Jr; Musumeci O; Shanske S; DiMauro S; Plotz P. 2001. Surprises of genetic engineering: a possible model of polyglucosan body disease. Neurology 56(12):1739-45. [PubMed: 11425943]  [MGI Ref ID J:117911]

Raben N; Hill V; Shea L; Takikita S; Baum R; Mizushima N; Ralston E; Plotz P. 2008. Suppression of autophagy in skeletal muscle uncovers the accumulation of ubiquitinated proteins and their potential role in muscle damage in Pompe disease. Hum Mol Genet 17(24):3897-908. [PubMed: 18782848]  [MGI Ref ID J:142536]

Raben N; Jatkar T; Lee A; Lu N; Dwivedi S; Nagaraju K; Plotz PH. 2002. Glycogen stored in skeletal but not in cardiac muscle in acid alpha-glucosidase mutant (Pompe) mice is highly resistant to transgene-encoded human enzyme. Mol Ther 6(5):601-8. [PubMed: 12409258]  [MGI Ref ID J:103961]

Raben N; Lu N; Nagaraju K; Rivera Y; Lee A; Yan B; Byrne B; Meikle PJ; Umapathysivam K; Hopwood JJ; Plotz PH. 2001. Conditional tissue-specific expression of the acid alpha-glucosidase (GAA) gene in the GAA knockout mice: implications for therapy. Hum Mol Genet 10(19):2039-47. [PubMed: 11590121]  [MGI Ref ID J:72192]

Raben N; Nagaraju K; Lee A; Lu N; Rivera Y; Jatkar T; Hopwood JJ; Plotz PH. 2003. Induction of tolerance to a recombinant human enzyme, acid alpha-glucosidase, in enzyme deficient knockout mice. Transgenic Res 12(2):171-8. [PubMed: 12739885]  [MGI Ref ID J:82912]

Raben N; Nagaraju K; Lee E; Plotz P. 2000. Modulation of disease severity in mice with targeted disruption of the acid alpha-glucosidase gene. Neuromuscul Disord 10(4-5):283-91. [PubMed: 10838256]  [MGI Ref ID J:76435]

Rucker M; Fraites TJ Jr; Porvasnik SL; Lewis MA; Zolotukhin I; Cloutier DA; Byrne BJ. 2004. Rescue of enzyme deficiency in embryonic diaphragm in a mouse model of metabolic myopathy: Pompe disease. Development 131(12):3007-19. [PubMed: 15169761]  [MGI Ref ID J:106533]

Schliselfeld LH; Danon MJ. 2002. Inverse relationship of skeletal muscle glycogen from wild-type and genetically modified mice to their phosphorylase a activity. Biochem Biophys Res Commun 290(2):874-7. [PubMed: 11785984]  [MGI Ref ID J:73924]

Sun B; Bird A; Young SP; Kishnani PS; Chen YT; Koeberl DD. 2007. Enhanced response to enzyme replacement therapy in Pompe disease after the induction of immune tolerance. Am J Hum Genet 81(5):1042-9. [PubMed: 17924344]  [MGI Ref ID J:135964]

Takikita S; Myerowitz R; Zaal K; Raben N; Plotz PH. 2009. Murine muscle cell models for Pompe disease and their use in studying therapeutic approaches. Mol Genet Metab 96(4):208-17. [PubMed: 19167256]  [MGI Ref ID J:146894]

Takikita S; Schreiner C; Baum R; Xie T; Ralston E; Plotz PH; Raben N. 2010. Fiber type conversion by PGC-1alpha activates lysosomal and autophagosomal biogenesis in both unaffected and Pompe skeletal muscle. PLoS One 5(12):e15239. [PubMed: 21179212]  [MGI Ref ID J:169000]

Taksir TV; Griffiths D; Johnson J; Ryan S; Shihabuddin LS; Thurberg BL. 2007. Optimized preservation of CNS morphology for the identification of glycogen in the Pompe mouse model. J Histochem Cytochem 55(10):991-8. [PubMed: 17510371]  [MGI Ref ID J:126885]

Wang W; Parker GE; Skurat AV; Raben N; DePaoli-Roach AA; Roach PJ. 2006. Relationship between glycogen accumulation and the laforin dual specificity phosphatase. Biochem Biophys Res Commun 350(3):588-92. [PubMed: 17022935]  [MGI Ref ID J:114495]

Xu S; Galperin M; Melvin G; Horowits R; Raben N; Plotz P; Yu L. 2010. Impaired organization and function of myofilaments in single muscle fibers from a mouse model of Pompe disease. J Appl Physiol 108(5):1383-8. [PubMed: 20223998]  [MGI Ref ID J:185846]

Zhu Y; Li X; McVie-Wylie A; Jiang C; Thurberg BL; Raben N; Mattaliano RJ; Cheng SH. 2005. Carbohydrate-remodelled acid alpha-glucosidase with higher affinity for the cation-independent mannose 6-phosphate receptor demonstrates improved delivery to muscles of Pompe mice. Biochem J 389(Pt 3):619-28. [PubMed: 15839836]  [MGI Ref ID J:117551]

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