Overview

Also Known As:CHCHD10^S55L

This CRISPR/Cas9 generated CHCHD10^S55L mutant on the C57BL/6NJ background of the of Chchd10 gene introduces the S55L knock-in mutation. These mice may be useful in studies related to mitochondrial bioenergetics and pathogenesis of diseases such as mitochondrial myopathy, motor neuron disease, frontotemporal dementia, Parkinson's disease, and amyotrophic lateral sclerosis.

Donating Investigator

Cathleen Lutz, The Jackson Laboratory

Genetic overview

Genetic Background	Generation

Chchd10^em8Lutzy

Allele Type	Gene Symbol	Gene Name
Endonuclease-mediated (Humanized sequence)	Chchd10	coiled-coil-helix-coiled-coil-helix domain containing 10

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Research Applications

Neurobiology Research
Internal/Organ Research
Cardiovascular Research
Developmental Biology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

CRISPR/cas9 endonuclease mediated genome editing of the Chchd10, coiled-coil-helix-coiled-coil-helix domain containing 10, gene was used to introduce the S55L knock in mutation (TCA -> TTA codon change) in exon 2. The mouse S55L mutation is equivalent to the human S59L mutation. The targeted Chchd10 gene encodes a mitochondrial intermembrane protein that is involved with mitochondrial cristae morphology and oxidative phosphorylation. Mutations in the human CHCHD10 gene can cause frontotemporal dementia and amyotrophic lateral sclerosis (ALS). Chchd10^S55L heterozygous mice have a shortened mean lifespan of approximately 344 days. Onset of body weight loss and progressive kyphosis is approximately 200 days of age in female heterozygotes and 125 days in male heterozygotes. Homozygotes exhibit a more severe body weight loss compared to heterozygotes. Muscle weakness is apparent at approximately 150 days of age with exercise intolerance, with evident muscle mass loss at 330 days of age. At approximately 260 days of age, heterozygotes exhibit motor deficit (forelimb grip strength) which progresses to abnormal gait. Hypertrophic cardiomyopathy is detected in heterozygotes at 330 days of age. Pregnant female heterozygotes exhibit accelerated mortality compared to virgin female heterozygotes. Histological analysis of heart tissue from breeding heterozygous females reveals cytoplasmic vacuoles, increased variation of the size of the nucleus, and fibrotic interstitial collagen accumulation. Cardiomyocyte ultrastructure is altered (increased number of mitochondria with abnormal features). The myofibers from gastrocnemius muscle exhibit splitting, increased number of atropic and angular fibers, increased nuclear density and central nuclei. Disorganized sarcomeres and increased number of abnormal mitochondria are also observed. Neuromuscular junction innervation and morphology is degenerated and abnormal: approximately 50% of neuromuscular junctions in Chchd10^S55L muscle show no innervation.

Development

The Chchd10 ^G56S allele was created by Dr. Cathleen Lutz (The Jackson Laboratory) using CRISPR/cas9 endonuclease-mediated genome editing in C57BL/6NJ mouse zygotes (Stock No. 005304).
Specifically, the coiled-coil-helix-coiled-coil-helix domain containing 10 locus (Chchd10) on chromosome 10 was targeted with single guide RNAs designed to substitute the TCA wild type serine codon with a TTA leucine codon (S55L) in exon 2.
The sgRNAs, an oligonucleotide sequence containing the S55L mutation, and cas9 endonuclease were electroporated into the cytoplasm of single cell C57BL/6NJ-derived zygotes containing well recognized pronuclei. Embryos were transferred to pseudopregnant females, and correctly targeted pups (identified by DNA sequencing) were bred to C57BL/6NJ (Stock# 005304) for germline transmission. Mice derived from founder 54 (GET473) were further bred to C57BL/6NJ inbred mice for 2 generations to develop the colony.

Control Suggestions

005304 C57BL/6NJ

Additional Information

Considerations for Choosing Controls

Selected References

Anderson CJ; Bredvik K; Burstein SR; Davis C; Meadows SM; Dash J; Case L; Milner TA; Kawamata H; Zuberi A; Piersigilli A; Lutz C; Manfredi G. 2019. ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response. Acta NeuropatholPubMed: 30877432 MGI: J:272524

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Genetics

Chchd10^em8Lutzy

Allele Symbol: Chchd10^em8Lutzy

Allele Name	endonuclease-mediated mutation 8, Cat Lutz
Allele Type	Endonuclease-mediated (Humanized sequence)
Allele Synonym(s)	CHCHD10^S55L
Gene Symbol and Name	Chchd10, coiled-coil-helix-coiled-coil-helix domain containing 10
Gene Synonym(s)
Strain of Origin	C57BL/6NJ
Chromosome	10
Molecular Note	CRISPR/Cas9 genome editing is used to substitute the TCA wild type serine codon with a TTA leucine codon (S55L) in exon 2. The mouse S55L mutation is equivalent to the human S59L mutation. Mutations in the human CHCHD10 gene can cause frontotemporal dementia and amyotrophic lateral sclerosis (ALS).

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Neurobiology Research
- Ataxia (Movement) Defects
Internal/Organ Research
- Skeleton
Cardiovascular Research
- Heart Abnormalities
  - cardiomyopathy
Developmental Biology Research

Mammalian Phenotype Terms by Genotype

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

Genotype: Chchd10^em8Lutzy/Chchd10⁺
C57BL/6NJ-Chchd10/J

cellular phenotype

abnormal mitochondrial matrix morphology
- matrix swelling in cardiac mitochondria

increased mitochondrial number
- increased proportion of mitochondria in heart

abnormal mitochondrial morphology
- increased proportion of mitochondria with abnormal vacuoles in soma of motor neurons
- abnormal mitochondria in TH+ dopaminergic neurons
- increased number of mitochondria with abnormal structure in sarcomeres
- matrix swelling, loss of cristae and abnormal membranous structures in cardiac mitochondria

abnormal vacuole morphology
- vacuoles are well defined, optically empty, and variably sized
- increased proportion of mitochondria with abnormal vacuoles in soma of motor neurons
- cytoplasmic vacuolization is observed in cardiomyocytes from the atria and ventricles

abnormal cell nucleus morphology
- increased variation of nuclear size in cardiomyocytes

abnormal mitochondrial crista morphology
- loss of cristae in cardiac mitochondria

growth/size/body region phenotype

weight loss
- body weight loss beginning at 200 days in females and 125 days in males

hearing/vestibular/ear phenotype

increased susceptibility to otitis media
- sterile otitis media
- effusion and accumulation of macrophages, neutrophils and degeneration of epithelial cells in tympanic bulla

homeostasis/metabolism phenotype

impaired exercise endurance
- exercise intolerance starting at 150 days of age

immune system phenotype

increased susceptibility to otitis media
- effusion and accumulation of macrophages, neutrophils and degeneration of epithelial cells in tympanic bulla
- sterile otitis media

mortality/aging

premature death
- shortened lifespan (344+/-6.7 days)

muscle phenotype

abnormal sarcomere morphology
- disorganization of sarcomeres, increased number of mitochondria with abnormal structure

centrally nucleated skeletal muscle fibers

abnormal skeletal muscle fiber morphology
- myofibers in muscle develop fiber splitting, increased variation in size, atrophic and angular fibers, increased nuclear density, and centrally located nuclei

decreased skeletal muscle mass
- decrease in muscle mass is observed at 330 days of age

nervous system phenotype

abnormal motor neuron morphology
- increased proportion of mitochondria with abnormal vacuoles in soma of motor neurons

abnormal neuromuscular synapse morphology
- loss of innervation of 50% of neuromuscular junction
- loss of complexity and reduced area in neuromuscular junctions

abnormal dopaminergic neuron morphology
- abnormal mitochondria in TH+ dopaminergic neurons; no loss of dopaminergic neurons is observed

skeleton phenotype

kyphosis
- severe kyphosis beginning at 200 days in females and 125 days in males

behavior/neurological phenotype

impaired exercise endurance
- exercise intolerance starting at 150 days of age

impaired limb coordination
- impaired limb coordination as determined by pole descent task at 330 days of age

limb grasping
- hind limb clasping is observed in pole descent task at 330 days of age

decreased grip strength
- decline in forelimb grip strength beginning at 260 days

decreased exploration in new environment
- decreased exploratory behavior in open-field test is observed at 250 days of age

abnormal gait
- abnormal gait characterized by widened stance and splayed hind limbs

cardiovascular system phenotype

cardiac interstitial fibrosis
- prominent cardiac interstitium

Genotype: Chchd10^em8Lutzy/Chchd10^em8Lutzy
C57BL/6NJ-Chchd10/J

behavior/neurological phenotype

impaired exercise endurance
- exercise intolerance is more severe in homozygotes than heterozygotes

decreased grip strength
- decline in forelimb grip strength is more severe in homozygotes than heterozygotes

growth/size/body region phenotype

weight loss
- body weight loss is more severe in homozygotes than heterozygotes

homeostasis/metabolism phenotype

impaired exercise endurance
- exercise intolerance is more severe in homozygotes than heterozygotes

mortality/aging

premature death
- shortened lifespan is more severe in homozygotes than heterozygotes

References

Anderson CJ; Bredvik K; Burstein SR; Davis C; Meadows SM; Dash J; Case L; Milner TA; Kawamata H; Zuberi A; Piersigilli A; Lutz C; Manfredi G. 2019. ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response. Acta NeuropatholPubMed: 30877432 MGI: J:272524

Additional - Chchd10^em8Lutzy related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- End Point Analysis:Chchd10-EP
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, heterozygous or homozygous males may be bred to female C57BL/6NJ (Stock# 005304) or female wildtype littermates. Pregnant female heterozygotes exhibit accelerated mortality.
- Additional Breeding and Husbandry Support
Mating System
- +/+ sibling x Heterozygote
- Inbred x Heterozygote
Citation
When using the CHCHD10^S55L mouse strain in a publication, please cite the originating article(s) and include JAX stock #028952 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 Chchd10<em8(S55L)Lutzy>

Payment Terms and Conditions

Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

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

The use of this mouse model is subject to the terms and conditions of the Limited License from The Broad Institute.

The use of this mouse model is subject to the terms and conditions of the Limited Use Label License from Caribou Biosciences, Inc.

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Also Known As:CHCHD10S55L

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Chchd10em8Lutzy

Allele Symbol: Chchd10em8Lutzy

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Chchd10em8Lutzy/Chchd10+C57BL/6NJ-Chchd10/J

cellular phenotype

growth/size/body region phenotype

hearing/vestibular/ear phenotype

homeostasis/metabolism phenotype

immune system phenotype

mortality/aging

muscle phenotype

nervous system phenotype

skeleton phenotype

behavior/neurological phenotype

cardiovascular system phenotype

Genotype: Chchd10em8Lutzy/Chchd10em8LutzyC57BL/6NJ-Chchd10/J

behavior/neurological phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

mortality/aging

References

Additional - Chchd10em8Lutzy related

Genotyping Protocols

Breeding Considerations

Mating System

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

Also Known As:CHCHD10^S55L

Chchd10^em8Lutzy

Allele Symbol: Chchd10^em8Lutzy

Genotype: Chchd10^em8Lutzy/Chchd10⁺
C57BL/6NJ-Chchd10/J

Genotype: Chchd10^em8Lutzy/Chchd10^em8Lutzy
C57BL/6NJ-Chchd10/J

Additional - Chchd10^em8Lutzy related