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 Vesa Kaartinen,   University of Michigan

Description
Mice with a null Aga gene, which encodes the lysosomal enzyme glycosylasparaginase, exhibit normal early development which slowly progresses to severe mental and motor retardation in early adulthood. At 5-10 months of age, massive accumulation of glycoaspartylglucosamine can be detected along with lysosomal vacuolization, axonal swelling in the gracile nucleus and impaired neuromotor coordination. After 10 months of age, there is progressive motor impairment and impaired bladder function and premature death.

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

Aspartylglucosaminuria; AGU - Models with phenotypic similarity to human disease where etiologies involve orthologs.1

1 Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Aga^tm1Vk/Aga^tm1Vk

        involves: 129S1/Sv * 129X1/SvJ * Black Swiss

• mortality/aging
• premature death
  • the first spontaneous deaths occur at 10 months   (MGI Ref ID J:91114)
  • the average lifespan of homozygous mutant mice is 19 months   (MGI Ref ID J:91114)
• behavior/neurological phenotype
• ataxia
  • older homozygotes (>18 months) show a severe ataxic gait   (MGI Ref ID J:91114)
• impaired balance
  • at 18 months or older, homozygotes exhibit great difficulty moving as well as poor balance   (MGI Ref ID J:91114)
• impaired coordination
  • at the age of 5 to 10 months, homozygotes exhibit impaired neuromotor coordination   (MGI Ref ID J:37022)
  • at 18 months or older, homozygotes show impaired neuromotor coordination   (MGI Ref ID J:91114)
• impaired limb coordination
  • at 18 months or older, homozygotes often drag their hind legs while walking   (MGI Ref ID J:91114)
• short stride length
  • older homozygotes (>18 months) display short steps and often walk straddle-legged   (MGI Ref ID J:91114)
• cellular phenotype
• abnormal lysosome morphology
  • a strong accumulation of hypertrophic lysosomes is noted in the deep cerebellar nuclei whereas only relatively minor changes are observed in the hippocampus   (MGI Ref ID J:49386)
  • as early as 5-10 months, homozygotes exhibit a massive accumulation of aspartylglucosamine along with lysosomal vacuolization   (MGI Ref ID J:37022)
  • at >18 months, homozygotes show widely distributed lysosomal hypertrophy both in the CNS and in visceral organs   (MGI Ref ID J:91114)
• homeostasis/metabolism phenotype
• abnormal urine homeostasis
  • complete glycosylasparaginase deficiency leads to accumulation of aspartylglucosamine in tissues and urine   (MGI Ref ID J:37022)
  • adult homozygotes receiving i.v. injections of recombinant glycosylasparaginase rapidly restore aspartylglucosamine to normal levels in non-neuronal tissues   (MGI Ref ID J:60272)
  • a single AGA injection reduced the amount of aspartylglucosamine in liver and spleen by 90% and 80%, respectively   (MGI Ref ID J:60272)
  • AGU pathophysiologic features were reversed in non-neuronal tissues over a 2-week period of enzyme therapy   (MGI Ref ID J:60272)
  • glycosylasparaginase activity increased to 10% of that in wild-type brain tissue and the accumulation of aspartylglucosamine was decreased by 20% in total brain of treated mice   (MGI Ref ID J:60272)
• • aspartylglucosaminuria
    • complete glycosylasparaginase deficiency leads to accumulation of aspartylglucosamine in urine   (MGI Ref ID J:37022)
  • colorless urine
    • urine inside dilatated bladders is clear, not due to bacterial infections   (MGI Ref ID J:91114)
• liver/biliary system phenotype
• multifocal hepatic necrosis
  • many terminally ill homozygotes suffer from massive coagulative hepatic necrosis caused by bacterial infections   (MGI Ref ID J:91114)
• renal/urinary system phenotype
• abnormal kidney calyx morphology
  • the caliceal mucosa is distended to one or two urothelial cells   (MGI Ref ID J:91114)
• abnormal renal glomerulus morphology
  • homozygotes display glomerular loss   (MGI Ref ID J:91114)
• abnormal urinary bladder urothelium morphology
  • the thickness of the urothelium varies with the degree of bladder distention, stretching to a thickness of two cells in the most distended area   (MGI Ref ID J:91114)
• abnormal urine homeostasis
  • complete glycosylasparaginase deficiency leads to accumulation of aspartylglucosamine in tissues and urine   (MGI Ref ID J:37022)
  • adult homozygotes receiving i.v. injections of recombinant glycosylasparaginase rapidly restore aspartylglucosamine to normal levels in non-neuronal tissues   (MGI Ref ID J:60272)
  • a single AGA injection reduced the amount of aspartylglucosamine in liver and spleen by 90% and 80%, respectively   (MGI Ref ID J:60272)
  • AGU pathophysiologic features were reversed in non-neuronal tissues over a 2-week period of enzyme therapy   (MGI Ref ID J:60272)
  • glycosylasparaginase activity increased to 10% of that in wild-type brain tissue and the accumulation of aspartylglucosamine was decreased by 20% in total brain of treated mice   (MGI Ref ID J:60272)
• • aspartylglucosaminuria
    • complete glycosylasparaginase deficiency leads to accumulation of aspartylglucosamine in urine   (MGI Ref ID J:37022)
  • colorless urine
    • urine inside dilatated bladders is clear, not due to bacterial infections   (MGI Ref ID J:91114)
• anuria
  • homozygotes fail to urinate, leading to a massive expansion of the bladder   (MGI Ref ID J:91114)
• distended urinary bladder
  • a significant number of older male homozygotes have massively swollen bladders   (MGI Ref ID J:37022)
• hydronephrosis
  • impaired bladder function and subsequent hydronephrosis are often associated with a reflux nephropathy   (MGI Ref ID J:91114)
• kidney atrophy
  • renal parenchyma is thinned   (MGI Ref ID J:91114)
• • renal tubule atrophy
    • homozygotes display tubular atrophy   (MGI Ref ID J:91114)
• neurogenic bladder
  • at >18 months, all aging homozygotes suffer from impaired bladder function   (MGI Ref ID J:91114)
  • as peripheral nerves remain unaffected, the "neurogenic bladder" phenotype is presumed to be secondary to the CNS defects   (MGI Ref ID J:91114)
• renal interstitial fibrosis
  • homozygotes exhibit interstitial fibrosis   (MGI Ref ID J:91114)
• nervous system phenotype
• abnormal axon morphology
  • at 5-10 months, homozygotes exhibit axonal swelling in the gracile nucleus   (MGI Ref ID J:37022)
• abnormal cerebellum morphology
  • homozygotes display cerebellar damage, manifested as severe loss of Purkinje cells, intensive astrogliosis, and vacuolation of neurons in deep cerebellar nuclei   (MGI Ref ID J:91114)
• • Purkinje cell degeneration
    • unlike AGU patients, where loss of Purkinje cells is scattered, homozygotes display widespread loss of Purkinje cells   (MGI Ref ID J:91114)
• astrocytosis
  • older mice (>18 months) show intensive astrogliosis   (MGI Ref ID J:91114)
• neurodegeneration
  • in older homozygotes (>18 months), severe neuronal vacuolation is often associated with neuronal loss   (MGI Ref ID J:91114)
  • neuronal vacuolation is pronounced in the lateral thalamic nuclei, medullary reticular nuclei, vestibular nuclei, inferior olivary complex, and deep cerebellar nuclei   (MGI Ref ID J:91114)
  • severe vacuolation of cells in the vestibular and cochlear nuclei may contribute to the impairment of neuromotor coordination   (MGI Ref ID J:91114)
• • Purkinje cell degeneration
    • unlike AGU patients, where loss of Purkinje cells is scattered, homozygotes display widespread loss of Purkinje cells   (MGI Ref ID J:91114)
• neurogenic bladder
  • at >18 months, all aging homozygotes suffer from impaired bladder function   (MGI Ref ID J:91114)
  • as peripheral nerves remain unaffected, the "neurogenic bladder" phenotype is presumed to be secondary to the CNS defects   (MGI Ref ID J:91114)
• integument phenotype
• disheveled coat
  • at ~5 months, homozygotes start to exhibit a general scruffiness, recognizable from their disheveled coat   (MGI Ref ID J:91114)

View Research Applications

Research Applications

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

Aga^tm1Vk related

Neurobiology Research
Metabolic Defects

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Agatm1Vk
Allele Name		targeted mutation 1, Vesa Kaartinen
Allele Type		Targeted (knock-out)
Common Name(s)		AGU; Aga-;
Mutation Made By		Vesa Kaartinen,   University of Michigan
Strain of Origin		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
ES Cell Line Name		R1
ES Cell Line Strain		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Gene Symbol and Name		Aga, aspartylglucosaminidase
Chromosome		8
Gene Common Name(s)		AGU; ASRG; AW060726; GA; expressed sequence AW060726;
Molecular Note		A neomycin selection cassette was inserted into the coding sequences in exon 3. Northern blot analysis and RT-PCR demonstrated that no detectable transcript is produced from this allele. Enzyme activity assays on liver and brain extracts of homozygous mice confirmed that no functional protein is made from this allele. [MGI Ref ID J:37022]

Genotyping

Genotyping Information

Genotyping Protocols

Aga^tm1Vk, Standard PCR
NEOTD (Generic Neo), Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Kaartinen V; Mononen I; Voncken JW; Noronkoski T; Gonzalez-Gomez I; Heisterkamp N; Groffen J. 1996. A mouse model for the human lysosomal disease aspartylglycosaminuria. Nat Med 2(12):1375-8. [PubMed: 8946839]  [MGI Ref ID J:37022]

Additional References

Aga^tm1Vk related

Dunder U; Kaartinen V; Valtonen P; Vaananen E; Kosma VM; Heisterkamp N; Groffen J; Mononen I. 2000. Enzyme replacement therapy in a mouse model of aspartylglycosaminuria. FASEB J 14(2):361-7. [PubMed: 10657992]  [MGI Ref ID J:60272]

Gonzalez-Gomez I; Mononen I; Heisterkamp N; Groffen J; Kaartinen V. 1998. Progressive neurodegeneration in aspartylglycosaminuria mice. Am J Pathol 153(4):1293-300. [PubMed: 9777961]  [MGI Ref ID J:91114]

Kaartinen V; Mononen I; Gonzalez-Gomez I; Noronkoski T; Heisterkamp N; Groffen J. 1998. Phenotypic characterization of mice with targeted disruption of glycosylasparaginase gene: a mouse model for aspartylglycosaminuria. J Inherit Metab Dis 21(3):207-9. [PubMed: 9686358]  [MGI Ref ID J:49386]

Kelo E; Dunder U; Mononen I. 2005. Massive accumulation of Man2GlcNAc2-Asn in nonneuronal tissues of glycosylasparaginase-deficient mice and its removal by enzyme replacement therapy. Glycobiology 15(1):79-85. [PubMed: 15342551]  [MGI Ref ID J:112542]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, RG10/RG30.

Colony Maintenance

Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls

General Supply Notes

• This strain is included in the Induced Mutant Resource Colony collection.
• Genomic DNA is available for this strain from the Mouse DNA Resource.

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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