Overview

Cln1^R151X mice contain a nonsense mutation similar to that found in patients with neuronal ceroid lipofuscinoses (NCLs).

Donating Investigator

David A. Pearce, Sanford School of Medicine of the University of South Dakota

Genetic overview

Genetic Background	Generation

Ppt1^tm1.1Dprc

Allele Type	Gene Symbol	Gene Name
Targeted (Humanized sequence)	Ppt1	palmitoyl-protein thioesterase 1

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Research Applications

Cell Biology Research
Developmental Biology Research
Neurobiology Research
Metabolism Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

Cln1^R151X mice contain the amino acid mutation R151X in exon 5 of the palmitoyl-protein thioesterase 1 (Ppt1) gene. CLN1 is a ubiquitous lysosomal enzyme responsible for removing palmitoyl groups from modified cysteine residues in polypeptides that have been targeted for degradation in the lysosome. Mutations in CLN1 most commonly lead to neuronal ceroid lipofuscinoses (NCL), autosomal recessive neurodegenerative disorder characterized by the progressive onset of seizures, blindness, motor and cognitive decline and premature death. These mutations most commonly lead to infantile NCL in which the patients exhibit microcephaly, seizures, motor abnormalities, ataxia and mental retardation leading to dementia, with death usually occurring by 8 to 13 years of age. Mutations can also lead to other clinical variants of NCL, such as variant forms of late-infantile NCL, juvenile NCL, and adult NCL.

In these mice, the R151X mutation introduces a nonsense mutation analogous to a Cln1 mutation commonly found patients with NCL. CLN1 proteins harboring the R151X mutation are targeted for degradation by the nonsense-mediated decay (NMD) pathway, leading to a significant decrease in CLN1 mRNA level and concurrent decrease in CLN1 enzyme activity in patient-derived lymphoblast cell lines. Tissues from heterozygous Cln1^R151X mice showed a 1.42- to 1.85-fold decrease in Cln1 expression and tissues from homozygotes showed a 5.32- to 12.99-fold decrease in Cln1 expression. Mice display significant motor deficits by 3 months of age. They also have significant accumulation of autofluorescent storage material within the cortex, thalamus and hippocampus at 5 months of age, consistent with the neuropathological hallmarks of infantile NCL disease.

Development

A targeting construct was designed to insert a C to T point mutation in exon 5 of the palmitoyl-protein thioesterase 1 (Ppt1) gene, resulting in a non-sense mutation, R151X, commonly found in humans with neuronal ceroid lipofuscinoses (NCLs). A loxP- and frt-flanked neomycin (neo) resistance cassette was inserted downstream of exon 5. This targeting construct was electroporated into 129S6/SvEv x C57BL/6J-derived embryonic stem (ES) cells and correctly targeted ES cells were injected into blastocysts. The resulting chimeric mice were bred to B6.C-Tg(CMV-cre)1Cgn/J (Stock No. 006054) to remove the floxed neo selection cassette, and offspring were crossed to remove the cre-expressing transgene. These Cln1^R151X mice were maintained on a mixed background. Upon arrival at The Jackson Laboratory, mice were bred to C57BL/6J (Stock No. 000664) for at least one generation to establish the colony.

Expression Data

Expressed Gene	Ppt1, palmitoyl-protein thioesterase 1, mouse, laboratory
Site of Expression

Control Suggestions

Approximate Controls

None Available

Additional Information

Considerations for Choosing Controls

Selected References

Miller JN; Kovacs AD; Pearce DA. 2015. The novel Cln1(R151X) mouse model of infantile neuronal ceroid lipofuscinosis (INCL) for testing nonsense suppression therapy. Hum Mol Genet 24(1):185-96PubMed: 25205113 MGI: J:213552

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Genetics

Ppt1^tm1.1Dprc

Allele Symbol: Ppt1^tm1.1Dprc

Allele Name	targeted mutation 1.1, David Pearce
Allele Type	Targeted (Humanized sequence)
Allele Synonym(s)	Cln1^R151X
Gene Symbol and Name	Ppt1, palmitoyl-protein thioesterase 1
Gene Synonym(s)
Expressed Gene	Ppt1, palmitoyl-protein thioesterase 1, mouse, laboratory
Strain of Origin	129S6/SvEvTac x C57BL/6J
Chromosome	4
Molecular Note	A targeting construct was designed to insert a C to T point mutation in exon 5 of the gene, resulting in a non-sense mutation, R151X, commonly found in humans with neuronal ceroid lipofuscinoses (NCLs). A loxP- and frt-flanked neomycin (neo) resistance cassette was inserted downstream of exon 5. Cre-mediated recombination removed the floxed neomycin cassette.

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 1

Research Areas By Phenotype

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

Cell Biology Research
- Protein Processing
  - degradation
Developmental Biology Research
- Neurodevelopmental Defects
Neurobiology Research
- Ataxia (Movement) Defects
- Cortical Defects
Metabolism Research
- Enzyme Deficiency

Mammalian Phenotype Terms by Genotype

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

Genotype: Ppt1^tm1.1Dprc/Ppt1^tm1.1Dprc
involves: 129S6/SvEvTac * BALB/cJ * C57BL/6

behavior/neurological phenotype

abnormal motor coordination/balance
- in a modified vertical pole test, 3 and 5 month old mutants climb down on the pole slower and turn downward on the pole slower than wild-type mice

decreased exploration in new environment
- males exhibit decreased exploration, staying in a large Petri dish longer than wild-type mice at 3 and 5 months of age

impaired coordination
- 3 month old mutants fall from the rotating rod sooner than wild-type mice, however performance is similar to wild-type mice at 5 months of age

nervous system phenotype

abnormal microglial cell activation
- cells have a macrophage-like appearance with rounded cell bodies and shortened processes in the cortex, thalamus and hippocampus
- mice exhibit an increase in CD68-positive cells in cortex, thalamus and hippocampus
- reactive microglia

astrocytosis
- astrocytes throughout the brain appear hypertrophied with enlarged cell soma and thickened processes as compared to controls
- mice exhibit an increase in GFAP immunoreactivity in the cortex, thalamus and hippocampus as compared to controls

pigmentation phenotype

lipofuscinosis
- autofluorescent storage material is observed in the cortex, thalamus and hippocampus of 5 month old mice

growth/size/body region phenotype

increased body weight
- mice are heavier at 3 months of age, however the weight difference is gone by 5 months of age

hematopoietic system phenotype

abnormal microglial cell activation
- cells have a macrophage-like appearance with rounded cell bodies and shortened processes in the cortex, thalamus and hippocampus
- mice exhibit an increase in CD68-positive cells in cortex, thalamus and hippocampus
- reactive microglia

immune system phenotype

abnormal microglial cell activation
- cells have a macrophage-like appearance with rounded cell bodies and shortened processes in the cortex, thalamus and hippocampus
- mice exhibit an increase in CD68-positive cells in cortex, thalamus and hippocampus
- reactive microglia

References

Miller JN; Kovacs AD; Pearce DA. 2015. The novel Cln1(R151X) mouse model of infantile neuronal ceroid lipofuscinosis (INCL) for testing nonsense suppression therapy. Hum Mol Genet 24(1):185-96PubMed: 25205113 MGI: J:213552

Additional - Ppt1^tm1.1Dprc related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Sanger sequencing:Ppt1
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, homozygous mice may be bred together.
- Additional Breeding and Husbandry Support
Citation
When using the STOCK Ppt1^tm1.1Dprc/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #026197 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 for Ppt1<tm1.1Dprc>

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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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Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Approximate Controls

Additional Information

Selected References

Ppt1tm1.1Dprc

Allele Symbol: Ppt1tm1.1Dprc

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: Ppt1tm1.1Dprc/Ppt1tm1.1Dprcinvolves: 129S6/SvEvTac * BALB/cJ * C57BL/6

behavior/neurological phenotype

nervous system phenotype

pigmentation phenotype

growth/size/body region phenotype

hematopoietic system phenotype

immune system phenotype

References

Additional - Ppt1tm1.1Dprc 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

Ppt1^tm1.1Dprc

Allele Symbol: Ppt1^tm1.1Dprc

Genotype: Ppt1^tm1.1Dprc/Ppt1^tm1.1Dprc
involves: 129S6/SvEvTac * BALB/cJ * C57BL/6

Additional - Ppt1^tm1.1Dprc related