Overview

Also Known As:Cln3deltaex7/8

These Cln3 knock-out mice exhibit retinal degeneration, neurodegeneration, and reduced survival.

Donating Investigator

Dr. Marcy E MacDonald, Massachusetts General Hospital

Genetic overview

Genetic Background	Generation

Cln3^tm1.1Mem

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Cln3	ceroid lipofuscinosis, neuronal 3, juvenile (Batten, Spielmeyer-Vogt disease)

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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 that are homozygous for the targeted mutation are viable and fertile, but have reduced survival, which drops to 80% by 12 months of age. Northern blot and RT PCR analyses of kidney, liver and brain tissue from homozygotes detect mutant mRNA. Truncated polypeptide and non-truncated alternatively spliced gene products are present. This 1.02kb deletion mutation replicates the most common mutation (>80%) found in Juvenile-onset neuronal ceroid lipofuscinosis (JNCL) patients. Autofluorescent lysosomal material containing immunoreactive ATPase subunit c are found in all tissues. Neuron and hepatocyte membrane deposits begin to accumulate as early as E19.5. Electron microscopic analysis reveals inclusions characteristic of JNCL tissue. Hypopigmented homozygotes exhibit retinal degeneration beginning at 10 months of age. Gliosis in the CNS and abnormal clasping behavior and gait traces indicate neurodegeneration. Onset and severity of disease phenotype is variable, which might be due to the mixed genetic background. Heterozygous mice do not display the phenotype. This mutant mouse strain may be useful in studies of Juvenile-onset neuronal ceroid lipofuscinosis (JNCL), Batten or Spielmeyer-Vogt disease.

Development

A targeting vector containing a loxP site flanked neomycin resistance gene driven by the mouse phosphoglycerate kinase promoter was used to disrupt exons 7 and 8 and adjacent non-coding sequence of the targeted gene. The construct was electroporated into 129-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts.

Control Suggestions

Wild-type from the colony

Additional Information

Considerations for Choosing Controls

Selected References

Cotman SL; Vrbanac V; Lebel LA; Lee RL; Johnson KA; Donahue LR; Teed AM; Antonellis K; Bronson RT; Lerner TJ; MacDonald ME. 2002. Cln3( Deltaex7/8) knock-in mice with the common JNCL mutation exhibit progressive neurologic disease that begins before birth. Hum Mol Genet 11(22):2709-21PubMed: 12374761 MGI: J:79615

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Genetics

Cln3^tm1.1Mem

Allele Symbol: Cln3^tm1.1Mem

Allele Name	targeted mutation 1.1, Marcy MacDonald
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Cln3^deltaex7/8
Gene Symbol and Name	Cln3, ceroid lipofuscinosis, neuronal 3, juvenile (Batten, Spielmeyer-Vogt disease)
Gene Synonym(s)
Strain of Origin	(129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Chromosome	7
Molecular Note	A floxed neo cassette that had replaced exons 7 and 8 was excised from Cln3^tm1Mem via in vivo cre mediated recombination in the germline. Expression analyses showed the presence of various aberrantly splice transcripts. Translation of a cDNA derived from RT-PCR analysis produced a protein containing the amino and carboxyl terminals as well as a novel mid-section. BLASTN revealed homology with a protein isolated from a patient with the juvenile-onset form of neuronal ceroid lipofuscinosis (JNCL).
Mutations Made By	Dr. Marcy MacDonald, Massachusetts General Hospital

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).

neuronal ceroid lipofuscinosis 3

Research Areas By Phenotype

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

Genotype: Cln3^tm1.1Mem related

Neurobiology Research
- Ataxia (Movement) Defects
- Metabolic Defects
- Neurodegeneration
- Neuromuscular defects

Mammalian Phenotype Terms by Genotype

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

Genotype: Cln3^tm1.1Mem/Cln3^tm1.1Mem
involves: 129S/SvEv * CD-1

behavior/neurological phenotype

abnormal gait
- at 10-12 months, gait analyses indicated shortened average stride length (rear paw) and increased base width (rear paw stance)

limb grasping
- at 10-12 months, tail hang/clasping assays revealed clasping in 42% of homozygous mutant mice, compared with 10% of wild-type or heterozygous mutant mice

short stride length
- at 10 -12 months of age

vision/eye phenotype

decreased retinal photoreceptor cell number
- at 10-17 months, retinas of hypopigmented homozygotes show a 37% reduction in the number of cone cells per field relative to retinas of hypopigmented heterozygotes

retinal degeneration
- retinas from pigmented homozygotes do not exhibit a cone cell loss at 10-17 months, suggesting that hypopigmentation may accelerate retinal degeneration

abnormal retinal neuronal layer morphology
- retinal neurons contain membrane deposits in the RGC layer and the inner nuclear layer (INL), with small punctate granules in the outer nuclear layer (ONL)
- punctate subunit c-reactive granules are noted within the ONL and INL in the mature retina at P8 and P30
- retinal deposits are first observed at P1.5, within the neuroblastic layer

abnormal retinal ganglion cell morphology
- retinal ganglion cells show electron-dense membranous perinuclear inclusions with a JNCL-like 'fingerprint' profile

liver/biliary system phenotype

abnormal hepatocyte morphology
- in liver, ATP synthase subunit c-reactive deposition is observed as early as E19.5
- at 10 months, mutant hepatocytes contain abundant autofluorescent, ATP synthase subunit c-reactive membrane deposits

mammalian phenotype

behavior/neurological phenotype
- Normal - no handling-induced seizures are observed

mortality/aging

premature death
- homozygotes show reduced (80%) survival, with the earliest death occurring at 7 months of age

nervous system phenotype

abnormal dentate gyrus morphology
- accumulates are first noted at E19.5 in neurons of the dentate gyrus and in the subventricular zone at the lateral ventricle
- in these regions, ATP synthase subunit c-reactive deposits are undetectable after P8

abnormal postnatal subventricular zone morphology
- in these regions, ATP synthase subunit c-reactive deposits are undetectable after P8
- accumulates are first noted at E19.5 in neurons of the dentate gyrus and in the subventricular zone at the lateral ventricle

abnormal hippocampus pyramidal cell morphology
- ultrastructurally, CA2/3 hippocampal pyramidal neurons show abundant perinuclear, osmiophilic and electron-dense inclusions
- such subunit-c inclusions have multilamellar membranes, a JNCL-like 'fingerprint' appearance, and are first detected at P8, increasing in size and intensity by P30

abnormal nervous system morphology
- at 10 months, homozygotes display membranous deposits in the CNS
- autofluorescent, ATP synthase subunit c-reactive membrane deposits are observed in the cytoplasm of CA2 and CA3 pyramidal cells of the hippocampus, Purkinje cells of the cerebellum, as well as cortical neurons and thalamic neurons

gliosis
- no apoptotic changes are observed in these regions
- at 10 months, all homozygotes exhibit reactive gliosis in the motor cortex, white matter tracts of the cerebellum and midbrain, including the inferior colliculus

decreased retinal photoreceptor cell number
- at 10-17 months, retinas of hypopigmented homozygotes show a 37% reduction in the number of cone cells per field relative to retinas of hypopigmented heterozygotes

abnormal cerebellar Purkinje cell layer
- cerebellar deposits are detected in the Purkinje cell layer at E19.5, increasing in severity by P30

abnormal retinal ganglion cell morphology
- retinal ganglion cells show electron-dense membranous perinuclear inclusions with a JNCL-like 'fingerprint' profile

References

Cotman SL; Vrbanac V; Lebel LA; Lee RL; Johnson KA; Donahue LR; Teed AM; Antonellis K; Bronson RT; Lerner TJ; MacDonald ME. 2002. Cln3( Deltaex7/8) knock-in mice with the common JNCL mutation exhibit progressive neurologic disease that begins before birth. Hum Mol Genet 11(22):2709-21PubMed: 12374761 MGI: J:79615

Additional - Cln3^tm1.1Mem related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Cln3alternate2
- Genotyping resources and troubleshooting
Breeding Considerations

The resulting line was then bred a CMV-cre transgenic strain to delete the neo cassette from the targeted allele. The strain is maintained on an outbred 129SvEv, CD1 background. When held in a live colony, it is maintained as a hemizygote.
- Additional Breeding and Husbandry Support
Citation
When using the Cln3deltaex7/8 mouse strain in a publication, please cite the originating article(s) and include JAX stock #004685 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 Homozygous for Cln3<tm1.1Mem>, 1 pair minimum

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Frozen Mouse Embryo	STOCK Cln3<tm1.1Mem>/J Frozen Embryos	$2595.00
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Frozen Mouse Embryo	STOCK Cln3<tm1.1Mem>/J Frozen Embryos	$3373.50
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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.

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Licensing Information

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Email: TechTran@jax.org

Also Known As:Cln3deltaex7/8

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Cln3tm1.1Mem

Allele Symbol: Cln3tm1.1Mem

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: Cln3tm1.1Mem related

Mammalian Phenotype Terms by Genotype

Genotype: Cln3tm1.1Mem/Cln3tm1.1Meminvolves: 129S/SvEv * CD-1

behavior/neurological phenotype

vision/eye phenotype

liver/biliary system phenotype

mammalian phenotype

mortality/aging

nervous system phenotype

References

Additional - Cln3tm1.1Mem 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

Licensing Information

Cln3^tm1.1Mem

Allele Symbol: Cln3^tm1.1Mem

Genotype: Cln3^tm1.1Mem related

Genotype: Cln3^tm1.1Mem/Cln3^tm1.1Mem
involves: 129S/SvEv * CD-1

Additional - Cln3^tm1.1Mem related