Overview

Also Known As:C9Orf72 null

Homozygous C9orf72 null mice exhibit lysosomal accumulation, altered immune responses in macrophages and microglia, as well as age-related neuro-inflammation similar to human C9orf72 amyotrophic lateral sclerosis (ALS). These mice may be useful in studying human ALS and frontotemporal dementia.

Donating Investigator

Robert H Baloh, Cedars Sinai Medical Center

Cathleen Lutz, The Jackson Laboratory

Genetic overview

Genetic Background	Generation

C9orf72^em5Lutzy

Allele Type	Gene Symbol	Gene Name
Endonuclease-mediated (Null/Knockout)	C9orf72	C9orf72, member of C9orf72-SMCR8 complex

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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

The most common genetic mutation associated with human amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide repeat expansion in a non-coding region of the chromosome 9 open reading frame 72 gene (C9orf72). Decreased expression of C9orf72 is seen in expansion carriers, suggesting loss of function may play a role in disease. The mouse 3110043O21Rik locus is the orthologue of human C9orf72.

The F12 C9orf72 null allele has a 79 bp deletion in exon 2 of the 3110043O21Rik locus (deletion extends from 38 nt upstream of ATG start codon in exon 2 to 38 nt downstream of the start codon [May 2020]). While mRNA expression levels from the mutant allele are similar to wildtype, western blot of brain lysates shows homozygous null F12 mice had complete loss of full-length C9orf72 protein. The presence/absence of proteins from any alternate transcripts identified more recently (e.g., transcript C9orf72-202 bypasses exon 2 and encodes a smaller 314 amino acid protein) has not been characterized to date (May 2020).

Homozygous mice are viable, fertile and develop normally, with no evidence of motor neuron disease or histological neurodegeneration through advanced age (17 months). Instead, C9orf72 null mice develop progressive splenomegaly and lymphadenopathy with accumulation of engorged macrophage-like cells. C9orf72 expression is normally highest in myeloid cells, and loss of C9orf72 in these C9orf72 null mice leads to lysosomal accumulation and altered immune responses in macrophages and microglia, with age-related neuroinflammation similar to C9orf72 ALS but not sporadic ALS patient tissue. The only histologic abnormalities exhibited in the nervous system of homozygous mice are rare chromatolytic structures in gray and white matter of the spinal cord, that did not increase with age or show reactive gliosis. Homozygotes exhibit no abnormalities in weight gain, lifespan, sensorimotor coordination, limb strength, muscle electrophysiology and femoral motor and sensory axon counts. [May 2016]

Development

The F12 C9orf72 null allele (exon 2 deletion; 3110043o21Rik^em5Lutzy) was created by Dr. Cat Lutz (The Jackson Laboratory) and Dr. Robert Baloh (Cedars-Sinai) using zinc finger nuclease (ZFN)-mediated genome editing in C57BL/6J mouse zygotes (Stock No. 000664).
Specifically, the 3110043O21Rik locus on chromosome 4 (orthologue of human C9orf72) was targeted by two ZFNs at the TGTTGC sequence located immediately downstream of the exon 2 ATG (GRCm38:4:35,218,827). Both ZFNs were microinjected in fertilized C57BL/6J oocytes and the live born were screened for deletions by loss-of-allele (LOA) assays designed with probes covering the respective cutting sites. Founders positive in the LOA screens were mated with wildtype C57BL/6J mice for germline transmission, and the progeny were sequenced at the locus targeted by the ZFN to map the deletions. The resulting F12 C9orf72 null mice have a 79 bp deletion in exon 2 (deletion extends from 38 nt upstream of ATG start codon in exon 2 to 38 nt downstream of the start codon [May 2020]). These mice were maintained on a C57BL/6J genetic background.

Expression Data

Expressed Gene	C9orf72, C9orf72, member of C9orf72-SMCR8 complex, mouse, laboratory
Site of Expression

Control Suggestions

Approximate Controls

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Genetics

C9orf72^em5Lutzy

Allele Symbol: C9orf72^em5Lutzy

Allele Name	endonuclease-mediated mutation 5, Cathy Lutz
Allele Type	Endonuclease-mediated (Null/Knockout)
Allele Synonym(s)	C9Orf72 null
Gene Symbol and Name	C9orf72, C9orf72, member of C9orf72-SMCR8 complex
Gene Synonym(s)
Expressed Gene	C9orf72, C9orf72, member of C9orf72-SMCR8 complex, mouse, laboratory
Strain of Origin	C57BL/6J
Chromosome	4
Molecular Note	The locus is targeted by two zinc finger nucleases (ZFNs) at the TGTTGC sequence located immediately downstream of the exon 2 ATG (GRCm38:4:35,218,827) resulting in a 79 bp deletion in exon 2 (38 bp upstream of the start codon and 38 bp downstream), which maps to mm10/GRCm38:4:35,218,896-35,218,822. Western blot of brain lysates shows homozygous null mice have complete loss of full-length protein, however, mRNA expression levels from the mutant allele are similar to wild type.

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Neurobiology Research
- Amyotrophic Lateral Sclerosis (ALS)

Mammalian Phenotype Terms by Genotype

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

Genotype: C9orf72^em5Lutzy/C9orf72^em5Lutzy
C57BL/6-C9orf72

cellular phenotype

lysosomal protein accumulation

mammalian phenotype

behavior/neurological phenotype
- Normal - mice exhibit no abnormalities in sensorimotor coordination, limb strength, and muscle electrophysiology

nervous system phenotype
- Normal - mice exhibit no abnormalities in femoral motor and sensory axon counts
- Normal - mice exhibit no evidence of motor neuron disease or histological neurodegeneration through advanced age (17 months)

nervous system phenotype

abnormal microglial cell physiology
- altered immune responses in microglia

abnormal spinal cord grey matter morphology
- chromatolytic structures are observed in gray and white matter of the spinal cord

abnormal spinal cord white matter morphology
- chromatolytic structures are observed in gray and white matter of the spinal cord

growth/size/body region phenotype

enlarged spleen

hematopoietic system phenotype

abnormal macrophage physiology
- altered immune responses in macrophages

abnormal microglial cell physiology
- altered immune responses in microglia

enlarged spleen

immune system phenotype

abnormal macrophage physiology
- altered immune responses in macrophages

abnormal microglial cell physiology
- altered immune responses in microglia

enlarged lymph nodes
- with accumulation of engorged macrophage-like cells

enlarged spleen

References

Additional - C9orf72^em5Lutzy related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:3110043o21Rik
- 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 C9Orf72 null mouse strain in a publication, please cite the originating article(s) and include JAX stock #027068 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 3110043021Rik<em5Lutzy>

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Also Known As:C9Orf72 null

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Approximate Controls

Additional Information

C9orf72em5Lutzy

Allele Symbol: C9orf72em5Lutzy

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: C9orf72em5Lutzy/C9orf72em5LutzyC57BL/6-C9orf72

cellular phenotype

mammalian phenotype

nervous system phenotype

growth/size/body region phenotype

hematopoietic system phenotype

immune system phenotype

References

Additional - C9orf72em5Lutzy 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

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

C9orf72^em5Lutzy

Allele Symbol: C9orf72^em5Lutzy

Genotype: C9orf72^em5Lutzy/C9orf72^em5Lutzy
C57BL/6-C9orf72

Additional - C9orf72^em5Lutzy related