Overview

Also Known As:Aga-

These Aga knock-out mice exhibit normal early development which slowly progresses to severe mental and motor retardation in early adulthood. They are suitable for use in applications related to the study of the human lysosomal disease aspartylglycosaminuria.

Donating Investigator

Dr. Vesa Kaartinen, University of Michigan

Genetic overview

Genetic Background	Generation

Aga^tm1Vk

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Aga	aspartylglucosaminidase

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Research Applications

Neurobiology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed 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. The mutant mice loose fertility earlier than the wild type siblings.

Selected References

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):1375-8PubMed: 8946839 MGI: J:37022

View All References

Genetics

Aga^tm1Vk

Allele Symbol: Aga^tm1Vk

Allele Name	targeted mutation 1, Vesa Kaartinen
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Aga-; AGU
Gene Symbol and Name	Aga, aspartylglucosaminidase
Gene Synonym(s)
Strain of Origin	(129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Chromosome	8
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.
Mutations Made By	Dr. Vesa Kaartinen, University of Michigan

Disease/Phenotype

Disease Terms

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).

aspartylglucosaminuria

Research Areas By Phenotype

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

Genotype: Aga^tm1Vk related

Neurobiology Research
- Metabolic Defects

Mammalian Phenotype Terms by Genotype

The following phenotype relates to a compound genotype created using this strain

Genotype: Aga^tm1Vk/Aga^tm1Vk
involves: 129S1/Sv * 129X1/SvJ * Black Swiss

behavior/neurological phenotype

ataxia
- older homozygotes (>18 months) show a severe ataxic gait

impaired balance
- at 18 months or older, homozygotes exhibit great difficulty moving as well as poor balance

impaired coordination
- at 18 months or older, homozygotes show impaired neuromotor coordination
- at the age of 5 to 10 months, homozygotes exhibit impaired neuromotor coordination

impaired limb coordination
- at 18 months or older, homozygotes often drag their hind legs while walking

short stride length
- older homozygotes (>18 months) display short steps and often walk straddle-legged

homeostasis/metabolism phenotype

abnormal urine homeostasis
- a single AGA injection reduced the amount of aspartylglucosamine in liver and spleen by 90% and 80%, respectively
- adult homozygotes receiving i.v. injections of recombinant glycosylasparaginase rapidly restore aspartylglucosamine to normal levels in non-neuronal tissues
- AGU pathophysiologic features were reversed in non-neuronal tissues over a 2-week period of enzyme therapy
- complete glycosylasparaginase deficiency leads to accumulation of aspartylglucosamine in tissues and urine
- 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

aspartylglucosaminuria
- complete glycosylasparaginase deficiency leads to accumulation of aspartylglucosamine in urine

colorless urine
- urine inside dilatated bladders is clear, not due to bacterial infections

integument phenotype

disheveled coat
- at ~5 months, homozygotes start to exhibit a general scruffiness, recognizable from their disheveled coat

liver/biliary system phenotype

multifocal hepatic necrosis
- many terminally ill homozygotes suffer from massive coagulative hepatic necrosis caused by bacterial infections

mortality/aging

premature death
- the average lifespan of homozygous mutant mice is 19 months
- the first spontaneous deaths occur at 10 months

nervous system phenotype

abnormal axon morphology
- at 5-10 months, homozygotes exhibit axonal swelling in the gracile nucleus

abnormal cerebellum morphology
- homozygotes display cerebellar damage, manifested as severe loss of Purkinje cells, intensive astrogliosis, and vacuolation of neurons in deep cerebellar nuclei

astrocytosis
- older mice (>18 months) show intensive astrogliosis

neurodegeneration
- in older homozygotes (>18 months), severe neuronal vacuolation is often associated with neuronal loss
- neuronal vacuolation is pronounced in the lateral thalamic nuclei, medullary reticular nuclei, vestibular nuclei, inferior olivary complex, and deep cerebellar nuclei
- severe vacuolation of cells in the vestibular and cochlear nuclei may contribute to the impairment of neuromotor coordination

neurogenic bladder
- as peripheral nerves remain unaffected, the "neurogenic bladder" phenotype is presumed to be secondary to the CNS defects
- at >18 months, all aging homozygotes suffer from impaired bladder function

Purkinje cell degeneration
- unlike AGU patients, where loss of Purkinje cells is scattered, homozygotes display widespread loss of Purkinje cells

renal/urinary system phenotype

abnormal kidney calyx morphology
- the caliceal mucosa is distended to one or two urothelial cells

abnormal renal glomerulus morphology
- homozygotes display glomerular loss

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

abnormal urine homeostasis
- a single AGA injection reduced the amount of aspartylglucosamine in liver and spleen by 90% and 80%, respectively
- adult homozygotes receiving i.v. injections of recombinant glycosylasparaginase rapidly restore aspartylglucosamine to normal levels in non-neuronal tissues
- AGU pathophysiologic features were reversed in non-neuronal tissues over a 2-week period of enzyme therapy
- complete glycosylasparaginase deficiency leads to accumulation of aspartylglucosamine in tissues and urine
- 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

anuria
- homozygotes fail to urinate, leading to a massive expansion of the bladder

aspartylglucosaminuria
- complete glycosylasparaginase deficiency leads to accumulation of aspartylglucosamine in urine

colorless urine
- urine inside dilatated bladders is clear, not due to bacterial infections

distended urinary bladder
- a significant number of older male homozygotes have massively swollen bladders

hydronephrosis
- impaired bladder function and subsequent hydronephrosis are often associated with a reflux nephropathy

kidney atrophy
- renal parenchyma is thinned

neurogenic bladder
- as peripheral nerves remain unaffected, the "neurogenic bladder" phenotype is presumed to be secondary to the CNS defects
- at >18 months, all aging homozygotes suffer from impaired bladder function

renal interstitial fibrosis
- homozygotes exhibit interstitial fibrosis

renal tubule atrophy
- homozygotes display tubular atrophy

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
- as early as 5-10 months, homozygotes exhibit a massive accumulation of aspartylglucosamine along with lysosomal vacuolization
- at >18 months, homozygotes show widely distributed lysosomal hypertrophy both in the CNS and in visceral organs

multifocal hepatic necrosis
- many terminally ill homozygotes suffer from massive coagulative hepatic necrosis caused by bacterial infections

References

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):1375-8PubMed: 8946839 MGI: J:37022

Additional - Aga^tm1Vk related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Aga
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, these mice can be bred as homozygotes.

The expected coat colors from breeding are white bellied agouti, and yellow with pink eyes.
- Additional Breeding and Husbandry Support
Citation
When using the Aga- mouse strain in a publication, please cite the originating article(s) and include JAX stock #003463 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous or wildtype for Aga<tm1Vk>

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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. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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Licensing Information

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Also Known As:Aga-

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Selected References

Agatm1Vk

Allele Symbol: Agatm1Vk

Disease Terms

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).

Research Areas By Phenotype

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

Genotype: Agatm1Vk related

Mammalian Phenotype Terms by Genotype

Genotype: Agatm1Vk/Agatm1Vkinvolves: 129S1/Sv * 129X1/SvJ * Black Swiss

behavior/neurological phenotype

homeostasis/metabolism phenotype

integument phenotype

liver/biliary system phenotype

mortality/aging

nervous system phenotype

renal/urinary system phenotype

cellular phenotype

References

Additional - Agatm1Vk related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Aga^tm1Vk

Allele Symbol: Aga^tm1Vk

Genotype: Aga^tm1Vk related

Genotype: Aga^tm1Vk/Aga^tm1Vk
involves: 129S1/Sv * 129X1/SvJ * Black Swiss

Additional - Aga^tm1Vk related