Overview

Also Known As:YG8sR

This human FXN YAC transgenic mouse model has the mouse frataxin knockout allele (Fxn^-) and the human FXN YAC transgene small repeat YG8s (contracted integration to a single copy of the human FXN gene with GAA trinucleotide repeats [~250-300]). Mice homozygous for the knockout and hemizygous for the YG8s transgene, called YG8sR mice, are rescued from knockout lethality and have transgene expression that models the phenotype of Friedreich's Ataxia (FRDA). Compared to other human FXN YAC transgenic rescue mouse models, the YG8sR model expresses a contracted human frataxin, resulting in much greater FXN deficiency. As such, the donating investigator concludes that YG8sR can be considered the most suitable YAC transgenic GAA repeat-based mouse model for the investigation of potential therapies for FRDA.

Our preclinical efficacy testing services offer scientific expertise and an array of target-based and phenotype-based outcome measures, both in vivo and at endpoint, for flexible study designs and assay development in mouse models of Friedreich's Ataxia. See our full service platform.

Donating Investigator

Mark A Pook, Brunel University

Genetic overview

Genetic Background	Generation

Tg(FXN)YG8Pook

Allele Type
Transgenic (Inserted expressed sequence, Humanized sequence)

Fxn^tm1Mkn

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Fxn	frataxin

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Research Applications

Neurobiology Research

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Base Price

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$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

This human FXN YAC transgenic mouse model has the mouse frataxin knockout allele (Fxn^-) and the YG8 small repeat human FXN YAC transgene (YG8s). The YG8s transgene has a contraction of the original YG8 transgene integration to a single copy. Like other GAA repeat mouse models, the YG8s transgene exhibits somatic GAA repeat instability. Upon arrival at The Jackson Laboratory in 2014, the transgene contained ~200 GAA repeats. Repeats are now in the 250-300 range (Jan 2017).

Compared to other human FXN YAC transgenic rescue mouse models, the YG8sR model expresses a contracted human frataxin, resulting in much greater FXN deficiency. As such, the donating investigator concludes that YG8sR can be considered the most suitable YAC transgenic GAA repeat-based mouse model for the investigation of potential therapies for Friedreich's Ataxia (FRDA).

Mice that are heterozygous for Fxn^- and hemizygous for the YG8s transgene are viable and fertile with normal lifespan. When singly homozygous for the frataxin knockout allele, mice are embryonic lethal. Mice homozygous for the knockout (Fxn^-/-) and hemizygous for the YG8s transgene, called YG8 small repeat human FXN YAC transgenic rescue mice (or YG8sR mice), exhibit an age-dependent GAA repeat expansion accumulation in the CNS (particularly cerebellum), progressive decrease in motor coordination and significant functional locomotor deficits; all similar to the human pathology of FRDA. YG8sR mice also exhibit glucose intolerance and insulin hypersensitivity. Of note, YG8sR mice have a progressive gain in weight compared to C57BL6/J mice (which may affect rotarod performance).

It should be noted that the YAC transgenic FRDA mouse models available from The Jackson Laboratory (YG22R, YG8R and YG8sR) may have different GAA repeat sizes than the animals used in the publications described below.
Publications from Dr. Mark A. Pook (Brunel University London) in 2014-2015 examine the correlation between the FRDA-like pathological phenotype and frataxin-deficiency in the YAC transgenic FRDA mouse models YG22R (two copies of the FRDA transgene; 190 GAA repeats expanded to ~170-260), YG8R (two copies of the FRDA transgene; 90-190 GAA repeats expanded to ~120-220) and YG8sR (a contraction of the transgene to a single copy; ~120-150 GAA repeats) compared to Y47R control mice (one copy of the FRDA transgene with a stable 9 GAA repeat) and C57BL6/J wildtype mice. The results described below are all in comparison to control mice.
The three YAC transgenic FRDA mouse models (YG8R, YG22R and YG8sR) had a progressive decrease in motor coordination; the degree of impairment was most significant in YG8R mice. All three models exhibited GAA repeat somatic instability in the brain, cerebellum and liver, as well as exhibited glucose intolerance and insulin hypersensitivity. The greatest FXN deficiency of the three models tested was in YG8sR. Expression levels of the transgenes in various tissues are reported in the Pook publications.

Development

This human FXN YAC transgenic mouse model has the mouse frataxin knockout allele (Fxn^+/-) and the YG8 small repeat human FXN YAC transgene (YG8s). When homozygous for the knockout and hemizygous for the transgene, these mice are called YG8 small repeat transgenic rescue mice (or YG8sR). Specific details below.

The frataxin knockout allele (Fxn^tm1Mkn) was designed by Drs. Michel Koenig and Helene Puccio to disrupt exon 4 and flanking sequences of the frataxin locus on chromosome 19 with a loxP-flanked PGK-neo cassette. The construct was electroporated into 129/Sv derived embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric animals were crossed to C57BL/6J mice, and then backcrossed to wildtype C57BL/6J mice. Heterozygous mice (Fxn^+/-) were used as described below. C57BL/6J-congenic frataxin knockout mice are described and available from The Jackson Laboratory as Stock No. 016842.

The YG8 human FXN YAC transgene was created by Dr. Mark A. Pook by first obtaining the 370 kbp YAC (Y37FA12) that includes the entire human FXN gene with nine GAA repeats [(GAA)₉] at the mutation locus within intron 1 of FXN. The GAA repeat expansion was modified to contain (GAA)₁₉₀. The modified YAC transgene was injected into the pronuclei of (C57BL/6 x CBA)F1 fertilized oocytes. Founder animals were bred to wildtype C57BL/6J mice. Founder line YG8 was established and backcrossed to wildtype C57BL/6J mice. YG8 mice initially contained an expansion of (GAA)_90-190, but was subsequently bred to contain (GAA)_120-220. YG8 mice have two tandem copies of the transgene integrated on mouse chromosome 16. Dr. Pook bred YG8 and Fxn^+/- mice together to generate the YG8R human FXN YAC transgenic mouse model (see Stock No. 012253). In 2012, Dr. Pook bred his colony of YG8R with Y47R control transgenic mice (Fxn^+/- mice containing the same human FXN YAC transgene with normal-sized (GAA)₉ repeats; see Stock No. 024097). The resulting animals contained a contraction of the transgene integration to a single copy with (GAA)₁₂₀; these animals were called YG8 small repeat human FXN YAC transgenic rescue mice (YG8sR). Like other GAA repeat mouse models, the YG8sR mice exhibit somatic GAA repeat instability. The GAA repeat size was expanded by selective breeding. In 2014, Dr. Pook sent YG8sR animals with ~200 GAA repeats on a "mixed-but-predominantly C57BL/6J" genetic background to The Jackson Laboratory as Stock No. 024113. Upon arrival, sperm was cryopreserved. To establish our living colony, an aliquot of the frozen sperm was used to fertilize oocytes from Fxn^+/- females (Stock No. 016842). In December 2014, a high density genome-wide scan showed that our live colony was 91-94% congenic on the C57BL/6J background. Please inquire about the current GAA repeat values.

Expression Data

Expressed Gene	FXN, frataxin, human
Site of Expression
Expressed Gene	Fxn, frataxin, mouse, laboratory
Site of Expression

Control Suggestions

Depending upon the experiment, the following may be an appropriate control:
--Heterozygous for Fxn^tm1Mkn, Noncarrier from the colony.
000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Anjomani Virmouni S; Ezzatizadeh V; Sandi C; Sandi M; Al-Mahdawi S; Chutake Y; Pook MA. 2015. A novel GAA-repeat-expansion-based mouse model of Friedreich's ataxia. Dis Model Mech 8(3):225-35PubMed: 25681319 MGI: J:217862

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Genetics

Tg(FXN)YG8Pook

Allele Symbol: Tg(FXN)YG8Pook

Allele Name	transgene insertion YG8, Mark A Pook
Allele Type	Transgenic (Inserted expressed sequence, Humanized sequence)
Allele Synonym(s)	YG8
Gene Symbol and Name	Tg(FXN)YG8Pook, transgene insertion YG8, Mark A Pook
Gene Synonym(s)
Promoter	FXN, frataxin, human
Expressed Gene	FXN, frataxin, human
Strain of Origin	CBA x C57BL/6
Chromosome	UN
General Note	Line YG22 exhibits slightly greater age-related repeat instability, with a bias toward repeat expansion.
Molecular Note	The transgenic construct consists of a 370kb YAC insert that includes the entire human FXN gene with GAA triplet repeat sequences, and was injected into fertilized CBA X C57BL/6 hybrid fertilized oocytes. Founder line YG8 was established, carrying 2 tandem copies of the human FXN gene with two GAA trinucleotide repeat sequences of 82 and 190 repeats. This line displayed a transmission rate of 52% to offspring.

Fxn^tm1Mkn

Allele Symbol: Fxn^tm1Mkn

Allele Name	targeted mutation 1, Michel Koenig
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Frda^-; Frda^del4
Gene Symbol and Name	Fxn, frataxin
Gene Synonym(s)
Expressed Gene	Fxn, frataxin, mouse, laboratory
Strain of Origin	129/Sv
Chromosome	19
Molecular Note	A loxP-flanked PGK-neomycin resistance cassette replaced a genomic DNA fragment containing exon 4, which is highly conserved and often mutated in humans. An additional line was also produced in which the loxP flanked neomycin cassette was removed by Cre mediated recombination, but no distinction was made between these alleles in the original reference. From J:90098: The presence of a human FRDA transgene in hemizygous form in a Frda^tm1Mkn homozygous null background rescues the embryonic lethal phenotype and complements for the loss of endogenous mouse frataxin.

Disease/Phenotype

Disease Terms

Characteristics of this human disease are associated with transgenes and other mutation types in the mouse.

Friedreich ataxia

Research Areas By Phenotype

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

Neurobiology Research
- Ataxia (Movement) Defects
- Friedreich's Ataxia
- 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: Fxn^tm1Mkn/Fxn^tm1Mkn Tg(FXN)YG8Pook/0
involves: 129/Sv * C57BL/6 * CBA

behavior/neurological phenotype

hypoactivity
- mice show a significant decrease in locomotor activity in the open field from 6 months of age

impaired coordination
- reduced rotarod performance is exhibited by mice from 3 months of age

mammalian phenotype

mortality/aging
- Normal - embryonic lethality seen for Fxn-deficient embryos is recued by transgene expression; normal numbers of offspring are recovered and mice show normal lifespans, surviving to at least 2 years of age

nervous system phenotype
- Normal - no neuronal histopathology is detected in cerebellar Purkinje cells or granule cells, and no abnormalities in brain or spinal cord regions are seen

muscle phenotype

abnormal myocardial fiber morphology
- patches of lipofuscin deposition and lysosymes, with accumulation of dispersed free glycogen disrupt regular arrangement of mitochondria within cardiomyocytes at 20 months

nervous system phenotype

abnormal action potential
- slight decrease in sensory action potential in 20-months old mice is detected, suggesting a mild progressive sensory neuropathy

abnormal axon morphology
- at 20 months, some axons in lumbar DRG display swelling and secondary demyelination

abnormal dorsal root ganglion morphology
- 16% of cervical DRG sections display vacuoles
- in mice >1 year of age, vacuoles are observed within the DRG in the cervical region

abnormal lumbar dorsal root ganglion morphology
- 70% of lumbar DRG sections examined have vacuoles
- prominent, giant vacuoles (round, singular or multiple) are observed in large sensory neuronal bodies of DRG in mice between 6 and 12 months, but not in controls; peripheral margination of nucleus in many large neuronal cell bodies with or without vacuoles
- s

brain inflammation
- cerebellum shows increased induction of inflammation in response to lipopolysaccharide (LPS) treatment

chromatolysis
- some regions of lumbar DRG are devoid of cytoplasmic organelles at 20 months

decreased nerve conduction velocity
- slight decrease in sensory nerve conduction velocity in 20-months old mice is detected, suggesting a mild progressive sensory neuropathy

neuron degeneration
- degenerating large DRG neurons are detected, with evidence of oxidative stress and mitochondrial dysfunction

cardiovascular system phenotype

abnormal myocardial fiber morphology
- patches of lipofuscin deposition and lysosymes, with accumulation of dispersed free glycogen disrupt regular arrangement of mitochondria within cardiomyocytes at 20 months

cellular phenotype

abnormal respiratory electron transport chain
- mitochondrial respiratory chain function is decreased compared to controls

oxidative stress
- in 6-9 month old animals, levels of oxidized proteins are increased, most significantly in cerebrum and cerebellum, with other significant increases seen in heart and skeletal muscle
- increased lipid peroxidation is detected in heart samples

growth/size/body region phenotype

increased body weight
- significant increase is observed from 9 months of age

homeostasis/metabolism phenotype

abnormal enzyme/coenzyme activity
- aconitase activity is decreased to <70% of wild-type levels

immune system phenotype

brain inflammation
- cerebellum shows increased induction of inflammation in response to lipopolysaccharide (LPS) treatment

References

Anjomani Virmouni S; Ezzatizadeh V; Sandi C; Sandi M; Al-Mahdawi S; Chutake Y; Pook MA. 2015. A novel GAA-repeat-expansion-based mouse model of Friedreich's ataxia. Dis Model Mech 8(3):225-35PubMed: 25681319 MGI: J:217862

Additional - Fxn^tm1Mkn related

Additional - Tg(FXN)YG8Pook related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Laragen
- Standard PCR:Tg(FXN) repeat copy number
- Standard PCR:Tg(FXN)YG8Pook GAA Repeat
- Standard PCR:Generic Human FXN
- Standard PCR:Generic Human FXN
- Standard PCR:Fxnalternate3
- QPCR:Tg(FXN)
- Genotyping resources and troubleshooting
Breeding Considerations

Mice that are heterozygous for the frataxin knockout allele (Fxn^tm1Mkn) and hemizygous for the YG8s transgene (Tg(FXN)YG8Pook) are viable and fertile with normal lifespan. Mice singly homozygous for Fxn^tm1Mkn are embryonic lethal - needing the presence of YG8s to rescue viability.

It is the experience at The Jackson Laboratory that breeding Fxn-deficient mice results in difficulty maintaining a large, sustainable live colony. As such, we maintain our live colony by breeding
mice heterozygous for Fxn^tm1Mkn and hemizygous for YG8s
to
mice wildtype at the Fxn locus and wildtype (noncarrier) for the transgene.
We also breed
mice heterozygous for Fxn^tm1Mkn and wildtype (noncarrier) for the transgene
to
mice wildtype at the Fxn locus and hemizygous for YG8s.

The resulting offspring will not be Fxn-deficient. Researchers will have to breed the mice with the desired genotype together to obtain the YG8s rescue animals (YG8sR; homozygous for the Fxn^tm1Mkn and hemizygous for YG8s).

The expected coat color is black.
- Additional Breeding and Husbandry Support
Mating System
- Heterozygous Hemizygous x Heterozygous Noncarrier or reciproca
Citation
When using the YG8sR mouse strain in a publication, please cite the originating article(s) and include JAX stock #024113 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 Fxn<tm1Mkn>., Hemizygous or non carrier for Tg(FXN)YG8Pook

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Also Known As:YG8sR

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Additional Information

Selected References

Tg(FXN)YG8Pook

Allele Symbol: Tg(FXN)YG8Pook

Fxntm1Mkn

Allele Symbol: Fxntm1Mkn

Disease Terms

Characteristics of this human disease are associated with transgenes and other mutation types in the mouse.

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Fxntm1Mkn/Fxntm1Mkn Tg(FXN)YG8Pook/0involves: 129/Sv * C57BL/6 * CBA

behavior/neurological phenotype

mammalian phenotype

muscle phenotype

nervous system phenotype

cardiovascular system phenotype

cellular phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

immune system phenotype

References

Additional - Fxntm1Mkn related

Additional - Tg(FXN)YG8Pook 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

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Fxn^tm1Mkn

Allele Symbol: Fxn^tm1Mkn

Genotype: Fxn^tm1Mkn/Fxn^tm1Mkn Tg(FXN)YG8Pook/0
involves: 129/Sv * C57BL/6 * CBA

Additional - Fxn^tm1Mkn related