Description

Strain Information

Former Names B6.Cg-Fxntm1Mkn Tg(FXN)YG8Pook/J    (Changed: 05-JUN-09 ) Type Congenic; Targeted Mutation; Transgenic; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Mating System See Colony Maintenance under the Health & husbandry tab         (Female x Male)   03-JUN-09 Species laboratory mouse Generation ?+F6 (20-SEP-11) Generation Definitions   Donating Investigator Mark Pook,   Brunel University

Description
Mice that are heterozygous for the targeted allele and hemizygous for the transgene are viable and fertile. High levels of human FXN gene product (mRNA or protein) are detected by RT-PCR and Western blot analysis. 40-50% of the endogenous mouse Fxn gene product (protein) is detected by Western blot analysis in mice heterozygous for the targeted mutation alone. The YG8 transgenic founder carries two tandem copies of the human FXN gene with two GAA triplet repeat sequences of 82 and 190 repeats. Mice that are homozygous for the targeted allele and hemizygous for the transgene exhibit an age dependent, tissue specific expansion of the GAA repeat, with expansion accumulation in the CNS (particularly cerebellum), similar to the human pathology. The GAA triplet repeat exhibits intergenerational instability. This mutant mouse strain may be useful in studies of Friedreich's Ataxia.

Importation of this model was supported by the Friedreichs Ataxia Research Alliance (FARA).

Development
These double mutant mice, heterozygous for the targeted mutation and hemizygous for the transgene, were generated by crossing transgenic mice (founder line YG8) with Fxn^tm1Mkn targeted mutant mice.

Drs. Michel Koenig and Helene Puccio generated the Fxn targeted mutation allele by disrupting exon 4 and flanking sequences 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 C57BL/6J for 5 generations.

The transgenic construct consisting of a 370kb YAC insert that includes the entire human FXN gene with GAA triplet repeat sequences, 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. Founder animals were bred to wildtype C57BL/6J mice for 5 generations.

The two lines were then crossed to generate the double mutant. The Donating Investigator breeds mice that are heterozygous for the Fxn^tm1Mkn targeted mutation and hemizygous for the YG8 transgene to mice that are heterozygous for the Fxn^tm1Mkn targeted mutation to obtain mice homozygous for the Fxn^tm1Mkn targeted mutation and hemizygous for the YG8 transgene.

SNP (single nucleotide polymorphism) analysis performed by The Jackson Laboratory revealed that this strain was on a mixed genetic background.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls

Related Strains

Strains carrying   Fxn^tm1Mkn allele

014162	B6.Cg-Fxntm1Mkn Fxntm1Pand/J
012910	B6.Cg-Fxntm1Mkn Tg(FXN)YG22Pook/J
012253	B6.Cg-Fxntm1Mkn Tg(FXN)YG8Pook/J
010963	STOCK Fxntm1Mkn Tg(FXN)YG22Pook/J

View Strains carrying   Fxn^tm1Mkn     (4 strains)

Strains carrying   Tg(FXN)YG8Pook allele

012253

B6.Cg-Fxntm1Mkn Tg(FXN)YG8Pook/J

View Strains carrying   Tg(FXN)YG8Pook     (1 strain)

Strains carrying other alleles of FXN

012910	B6.Cg-Fxntm1Mkn Tg(FXN)YG22Pook/J
012253	B6.Cg-Fxntm1Mkn Tg(FXN)YG8Pook/J
010963	STOCK Fxntm1Mkn Tg(FXN)YG22Pook/J

View Strains carrying other alleles of FXN     (3 strains)

Strains carrying other alleles of Fxn

011113	B6.129-Fxntm1.1Pand/J
008470	B6.129-Fxntm1Pand/J
014162	B6.Cg-Fxntm1Mkn Fxntm1Pand/J
012910	B6.Cg-Fxntm1Mkn Tg(FXN)YG22Pook/J
012253	B6.Cg-Fxntm1Mkn Tg(FXN)YG8Pook/J
010963	STOCK Fxntm1Mkn Tg(FXN)YG22Pook/J

View Strains carrying other alleles of Fxn     (6 strains)

Strains carrying other alleles of Tg(FXN)YG8Pook

012253

B6.Cg-Fxntm1Mkn Tg(FXN)YG8Pook/J

View Strains carrying other alleles of Tg(FXN)YG8Pook     (1 strain)

Additional Web Information

JAX^® NOTES, Fall 2008; 511. The Jackson Laboratory enters partnership to fight Friedreich's Ataxia.

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

Friedreich Ataxia 1; FRDA - Models with phenotypic similarity to human disease where etiologies involve orthologs.1

1 Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Fxn^tm1Mkn/Fxn^tm1Mkn Tg(FXN)YG8Pook/0

        involves: 129/Sv * C57BL/6 * CBA

• mortality/aging
• *normal* mortality/aging
  • 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   (MGI Ref ID J:114840)
• growth/size phenotype
• increased body weight
  • significant increase is observed from 9 months of age   (MGI Ref ID J:114840)
• nervous system phenotype
• *normal* nervous system phenotype
  • no neuronal histopathology is detected in cerebellar Purkinje cells or granule cells, and no abnormalities in brain or spinal cord regions are seen   (MGI Ref ID J:114840)
• • abnormal action potential
    • slight decrease in sensory action potential in 20-months old mice is detected, suggesting a mild progressive sensory neuropathy   (MGI Ref ID J:114840)
  • abnormal axon morphology
    • at 20 months, some axons in lumbar DRG display swelling and secondary demyelination   (MGI Ref ID J:114840)
  • abnormal dorsal root ganglion morphology
    • in mice >1 year of age, vacuoles are observed within the DRG in the cervical region   (MGI Ref ID J:114840)
    • 16% of cervical DRG sections display vacuoles   (MGI Ref ID J:114840)
  • • abnormal lumbar dorsal root ganglion morphology
      • 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   (MGI Ref ID J:114840)
      • 70% of lumbar DRG sections examined have vacuoles   (MGI Ref ID J:114840)
  • chromatolysis
    • some regions of lumbar DRG are devoid of cytoplasmic organelles at 20 months   (MGI Ref ID J:114840)
  • neuron degeneration
    • degenerating large DRG neurons are detected, with evidence of oxidative stress and mitochondrial dysfunction   (MGI Ref ID J:114840)
  • reduced nerve conduction velocity
    • slight decrease in sensory nerve conduction velocity in 20-months old mice is detected, suggesting a mild progressive sensory neuropathy   (MGI Ref ID J:114840)
• behavior/neurological phenotype
• hypoactivity
  • mice show a significant decrease in locomotor activity in the open field from 6 months of age   (MGI Ref ID J:114840)
• impaired coordination
  • reduced rotarod performance is exhibited by mice from 3 months of age   (MGI Ref ID J:114840)
• 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   (MGI Ref ID J:114840)
• cellular phenotype
• abnormal aerobic energy metabolism
  • mitochondrial respiratory chain function is decreased compared to controls   (MGI Ref ID J:114840)
• 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   (MGI Ref ID J:114840)
  • increased lipid peroxidation is detected in heart samples   (MGI Ref ID J:114840)
• 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   (MGI Ref ID J:114840)
• homeostasis/metabolism phenotype
• abnormal enzyme/coenzyme activity
  • aconitase activity is decreased to <70% of wild-type levels   (MGI Ref ID J:114840)

View Research Applications

Research Applications

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

Mouse/Human Gene Homologs

Neurobiology Research
Ataxia (Movement) Defects
Friedreich's Ataxia
Neurodegeneration

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Fxntm1Mkn
Allele Name		targeted mutation 1, Michel Koenig
Allele Type		Targeted (knock-out)
Common Name(s)		Frda-; Frdadel4;
Strain of Origin		129/Sv
Gene Symbol and Name		Fxn, frataxin
Chromosome		19
Gene Common Name(s)		CyaY; FA; FARR; FRDA; Frda; Friedreich ataxia; RGD1565754; X25;
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 Cremediated 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 Frdatm1Mkn homozygous null background rescues the embryonic lethal phenotype and complements for the loss of endogenous mouse frataxin. [MGI Ref ID J:62185]
Allele Symbol		Tg(FXN)YG8Pook
Allele Name		transgene insertion YG8, Mark A Pook
Allele Type		Transgenic (random, expressed)
Common Name(s)		YG8;
Strain of Origin		CBA x C57BL/6
Expressed Gene		FXN, frataxin, human
Promoter		FXN, frataxin, human
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. [MGI Ref ID J:91581]

Genotyping

Genotyping Information

Genotyping Protocols

Tg(FXN)YG8Pook GAA Repeat, Standard PCR
Tg(FXN)YG8Pook, QPCR
Fxn^suptm1Pand^/sup, Melt Curve Analysis
Fxn^tm1Mkn, Standard PCR
Fxn^tm1Pand GAA repeats, Standard PCR
Fxn^tm1Pand, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Al-Mahdawi S; Pinto RM; Ruddle P; Carroll C; Webster Z; Pook M. 2004. GAA repeat instability in Friedreich ataxia YAC transgenic mice. Genomics 84(2):301-10. [PubMed: 15233994]  [MGI Ref ID J:91581]

Al-Mahdawi S; Pinto RM; Varshney D; Lawrence L; Lowrie MB; Hughes S; Webster Z; Blake J; Cooper JM; King R; Pook MA. 2006. GAA repeat expansion mutation mouse models of Friedreich ataxia exhibit oxidative stress leading to progressive neuronal and cardiac pathology. Genomics 88(5):580-90. [PubMed: 16919418]  [MGI Ref ID J:114840]

Cossee M; Puccio H; Gansmuller A; Koutnikova H; Dierich A; LeMeur M; Fischbeck K; Dolle P; Koenig M. 2000. Inactivation of the Friedreich ataxia mouse gene leads to early embryonic lethality without iron accumulation. Hum Mol Genet 9(8):1219-26. [PubMed: 10767347]  [MGI Ref ID J:62185]

Additional References

Fxn^tm1Mkn related

Miranda CJ; Santos MM; Ohshima K; Smith J; Li L; Bunting M; Cossee M; Koenig M; Sequeiros J; Kaplan J; Pandolfo M. 2002. Frataxin knockin mouse. FEBS Lett 512(1-3):291-7. [PubMed: 11852098]  [MGI Ref ID J:109164]

Sandi C; Pinto RM; Al-Mahdawi S; Ezzatizadeh V; Barnes G; Jones S; Rusche JR; Gottesfeld JM; Pook MA. 2011. Prolonged treatment with pimelic o-aminobenzamide HDAC inhibitors ameliorates the disease phenotype of a Friedreich ataxia mouse model. Neurobiol Dis 42(3):496-505. [PubMed: 21397024]  [MGI Ref ID J:172875]

Santos MM; Miranda CJ; Levy JE; Montross LK; Cossee M; Sequeiros J; Andrews N; Koenig M; Pandolfo M. 2003. Iron metabolism in mice with partial frataxin deficiency. Cerebellum 2(2):146-53. [PubMed: 12880182]  [MGI Ref ID J:112348]

Sarsero JP; Li L; Holloway TP; Voullaire L; Gazeas S; Fowler KJ; Kirby DM; Thorburn DR; Galle A; Cheema S; Koenig M; Williamson R; Ioannou PA. 2004. Human BAC-mediated rescue of the Friedreich ataxia knockout mutation in transgenic mice. Mamm Genome 15(5):370-82. [PubMed: 15170226]  [MGI Ref ID J:90098]

Tg(FXN)YG8Pook related

Sandi C; Pinto RM; Al-Mahdawi S; Ezzatizadeh V; Barnes G; Jones S; Rusche JR; Gottesfeld JM; Pook MA. 2011. Prolonged treatment with pimelic o-aminobenzamide HDAC inhibitors ameliorates the disease phenotype of a Friedreich ataxia mouse model. Neurobiol Dis 42(3):496-505. [PubMed: 21397024]  [MGI Ref ID J:172875]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX12

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice can be bred as heterozygotes for the targeted mutation and hemizygotes for the transgene.
Mating System	See Colony Maintenance under the Health & husbandry tab         (Female x Male)   03-JUN-09
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls

General Supply Notes

• This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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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.

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