Overview

The ENU-induced neurological 7 (nur7) allele of aspartoacylase (Aspa^nur7) results from a Q193X transition generating a nonsense codon and a loss-of-function mutation. Homozygous Aspa^nur7 mice display a Canavan disease-related pathology and may be useful in studying the axonal pathology caused by central nervous system myelin defects.

Donating Investigator

Brian Popko, University of Chicago

Genetic overview

Genetic Background	Generation

Aspa^nur7

Allele Type	Gene Symbol	Gene Name
Chemically induced (ENU)	Aspa	aspartoacylase

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Research Applications

Research Tools
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 homozygous for this ENU-induced mutation, the neurological 7 (nur7) allele of Aspa (Aspa^nur7), are viable and fertile, although the donating investigator reports homozygotes are poor breeders. The Aspa^nur7 mutation encodes a Q193X transition that generates a nonsense codon and results in a predicted 120 amino acid truncation of the protein. While mutant Aspa mRNA expression is reduced by 40% (compared to wildtype), no truncated Aspa protein expression is reported in homozygous oligodendrocytes or brain tissue. Homozygous mice display early-onset spongy degeneration of central nervous system myelin with increased NAA levels similar to that observed in Canavan disease; an Aspa-deficiency-induced fatal childhood autosomal recessive leukodystrophy. Homozygous mice are easily distinguished at 21 days of age by their small body size and a wide-based ataxic gait. Neurological disease progresses with age to tremors and seizures. These Aspa^nur7 mutant mice may be useful in studying the axonal pathology caused by central nervous system myelin defects.

Development

These mutant mice were created by the laboratory of Dr. Monica Justice (Baylor College of Medicine) using multidose N-ethyl-N-nitrosourea (ENU) treatments to induce mutations in founder C57BL/6J mice. Genetic screening was utilized to identify mice with a neurological phenotype described as hypoactive in young postnatal mice and trembling during movement in adulthood ("small, lethargic, tremors in adults"). Using a candidate gene approach, a region of chromosome 11 containing the aspartoacylase (Aspa) gene was associated with the mutant phenotype. Sequencing of this gene identified a C->T transition in nucleotide 577 in exon 4 (coding a Q193X mutation that generates a TAA stop/nonsense codon and results in the early termination of the protein). Heterozygous Aspa^nur7 mice (also harboring the In(11Trp53;11Wnt3)8Brd balancer) were bred together (C57BL/6J genetic background) for many generations. Homozygous Aspa^nur7 mice (not harboring the In(11Trp53;11Wnt3)8Brd balancer) were sent to The Jackson Laboratory. Upon arrival, mice were bred with C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish the colony.

A 27 SNP (single nucleotide polymorphism) panel analysis performed by The Jackson Laboratory revealed 7 of 27 markers that were not C57BL/6 allele-type. These data suggest 129, C3H, or CBA (and perhaps other) genetic contamination prior to arrival at The Jackson Laboratory.

Control Suggestions

Wild-type from the colony
000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Kile BT; Hentges KE; Clark AT; Nakamura H; Salinger AP; Liu B; Box N; Stockton DW; Johnson RL; Behringer RR; Bradley A; Justice MJ. 2003. Functional genetic analysis of mouse chromosome 11. Nature 425(6953):81-6PubMed: 12955145 MGI: J:85113
Traka M; Wollmann RL; Cerda SR; Dugas J; Barres BA; Popko B. 2008. Nur7 is a nonsense mutation in the mouse aspartoacylase gene that causes spongy degeneration of the CNS. J Neurosci 28(45):11537-49PubMed: 18987190 MGI: J:143201

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Genetics

Aspa^nur7

Allele Symbol: Aspa^nur7

Allele Name	neurological 7
Allele Type	Chemically induced (ENU)
Allele Synonym(s)	neurological (nur) 07; nur^m07Jus; small lethargic
Gene Symbol and Name	Aspa, aspartoacylase
Gene Synonym(s)
Strain of Origin	C57BL/6J
Chromosome	11
Molecular Note	Exon 4 contains a point mutation of C to T at position 577 that results in an amino acid substitution of a stop codon for glutamine at position 193 (Q193X). The absence of protein expression was confirmed by western blot on brain extracts.

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).

Canavan disease

Research Areas By Phenotype

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

Research Tools
- Genetics Research
  - Mutagenesis and Transgenesis: Production of Chemical Mutations
  - Mutagenesis and Transgenesis
- Neurobiology Research
Neurobiology Research
- Neurodegeneration
- Myelination Defects
- Tremor Defects
- Ataxia (Movement) Defects
- Epilepsy
- Neuromuscular defects

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Aspa^nur7/Aspa^nur7
involves: C57BL/6J

behavior/neurological phenotype

tremors
- adult mice tremble during movement
- late onset; develop upon movement
- at P70, tremors are slightly increased compared to in younger mice
- mice develop more severe tremors as they age

impaired coordination
- latency to fall off the rotating rod is reduced by about 50%
- at P42 to P56, mice exhibit a 50% decreased in latency to fall on a rotarod compared to wild-type mice

seizures
- as mice age

abnormal gait
- at P21, mice exhibit a wide ataxic gait

hypoactivity
- animals have reduced open field activity
- young mice are hypoactive
- total distance traveled by mice is reduced

lethargy

ataxia
- at P21, mice exhibit a wide ataxic gait
- at P70, ataxia is slightly increased compared to in younger mice

decreased vertical activity

growth/size/body region phenotype

decreased body weight

decreased body size
- affected animals are smaller than littermates

homeostasis/metabolism phenotype

abnormal sphingolipid level
- mice exhibit abnormal sphingolipid composition, showing a reduction in the concentration of nonhydroxylated fatty acid containing GalC (NFA-GalC) in the brain at P21 and P60, whereas 2-hydroxylated fatty acid-containing GalC (HFA-GalC) levels are reduced to a lesser extent at P60

abnormal enzyme/coenzyme level
- N-acetylaspartate levels are increased in the brain

mortality/aging

premature death
- majority of mice die within 4 weeks

nervous system phenotype

brain vacuoles
- in wild-type mice
- at P70, the dorsal pons is more severely affected than the rest of the pons by vacuolization
- vacuoles are seen as swollen axons surrounded by compressed myelin layers
- at P70, vacuolization expands into subcortical white matter, brainstem, cerebellum and spinal cord gray matter
- lateral sections of the cerebellar sagittal plane exhibit more increasingly severe white matter lesions
- at P14, vacuoles are detected in the cerebellar white matter in the Purkinje cell layer and brainstem unlike in wild-type mice
- vacuolization is caused by the splitting of the myelin sheath
- vacuolation in the corpus callosum at P21 is less intense than in other white matter tracts
- vacuolation in the corpus callosum is less severe at P60 compared with P21 and almost undetectable in 1 year old mice
- mice exhibit progressive vacuolar degeneration that affects the forebrain, cerebral cortex, hippocampus, subcortical white matter regions, midbrain, pons and cerebellum where the granule cell layer, Purkinje cell layer and white matter show defects unlike in wild-type mice

abnormal myelination
- at P21, mice exhibit a 40% decrease in phosphatidyl ethanolamine in myelin compared to in wild-type mice
- at P21, normal fatty acid-containing Galc cerebroside is reduced 40% compared to in wild-type mice
- Normal - however, the level of hydroxyl fatty acid-containing Galc cerebroside is normal
- myelin degeneration is more pronounced at P70 than at P21
- at P21, myelin sheath thickness is reduced compared to in wild-type mice

spongiform encephalopathy
- beginning at P14, mice exhibit progressive spongiform degeneration
- massive spongy degeneration of white matter in the cerebellum, most pronounced around the deep cerebellar nuclei and less prominent within the folial white matter
- spongy degeneration worsens with age
- within the corpus callosum, white matter degeneration mainly affects the immediate subcortical callosal surface
- mice exhibit progressive neuropathy similar to in Aspa^nur7/Aspa^nur7 Ugt8a^tm1Pop/Ugt8a⁺ mice

abnormal oligodendrocyte morphology
- at P30, oligodendrocyte loss occurs in the spinal cord gray matter unlike in wild-type mice
- at P70, the number of oligodendrocytes is increased in the brainstem (medial pons) and spinal cord gray matter
- at P21, loss of oligodendrocytes occurs in lesion areas unlike in wild-type mice

astrocytosis

demyelination

enlarged lateral ventricles
- widened at P70

axon degeneration
- at P120, 30% fewer axons are found in the cerebellar white matter compared to in heterozygous mice

seizures
- as mice age

abnormal brain morphology
- N-acetylaspartate-derived neuropeptide NAAG levels are reduced by 25% in 1 year old brains

abnormal brain white matter morphology
- white matter degeneration in the cerebellum, corpus callosum, and other brain regions

References

Kile BT; Hentges KE; Clark AT; Nakamura H; Salinger AP; Liu B; Box N; Stockton DW; Johnson RL; Behringer RR; Bradley A; Justice MJ. 2003. Functional genetic analysis of mouse chromosome 11. Nature 425(6953):81-6PubMed: 12955145 MGI: J:85113
Traka M; Wollmann RL; Cerda SR; Dugas J; Barres BA; Popko B. 2008. Nur7 is a nonsense mutation in the mouse aspartoacylase gene that causes spongy degeneration of the CNS. J Neurosci 28(45):11537-49PubMed: 18987190 MGI: J:143201

Additional - Aspa^nur7 related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Sanger sequencing:Aspa-SEQ
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, heterozygous mice may be bred. The donating investigator reports that homozygous mice are poor breeders.
- Additional Breeding and Husbandry Support
Citation
When using the STOCK Aspa^nur7/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #008607 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

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Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
> >	Heterozygous for Aspa<nur7>

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The Jackson Laboratory's Genotype Promise

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.

Terms Of Use

General Terms and Conditions

Questions about Terms of Use

Additional Use Restrictions Apply

Use of MICE by companies or for-profit entities requires a license prior to shipping.

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Aspanur7

Allele Symbol: Aspanur7

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:

Mammalian Phenotype Terms by Genotype

Genotype: Aspanur7/Aspanur7involves: C57BL/6J

behavior/neurological phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

mortality/aging

nervous system phenotype

References

Additional - Aspanur7 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

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

Aspa^nur7

Allele Symbol: Aspa^nur7

Genotype: Aspa^nur7/Aspa^nur7
involves: C57BL/6J

Additional - Aspa^nur7 related