Overview

Tor1a^ΔE mice contain a pathogenic glutamic acid residue deletion in the Tor1a gene, making this stain useful for studying DYT1 dystonia.

Donating Investigator

William Dauer, University of Michigan Medical School

Genetic overview

Genetic Background	Generation

Tor1a^tm2Wtd

Allele Type	Gene Symbol	Gene Name
Targeted (Hypomorph)	Tor1a	torsin family 1, member A (torsin A)

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Research Applications

Neurobiology 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

Tor1a^ΔE mice contain a pathogenic glutamic acid residue deletion in exon 5 of the torsin family 1, member A (torsin A) (Tor1a) gene, resulting in the ΔE knockin. TOR1A is an ATPases Associated with diverse Activities (AAA⁺) protein residing in the lumen of the ER/nuclear envelope (ER/NE) space. The in-frame ΔE deletion in TOR1A has been shown to cause the autosomal dominant disorder, DYT1 dystonia, which is characterized by abnormal, involuntary twisting movements and muscle contractions due to selective dysfunction of CNS motor circuits. Mice that are homozygous for this allele die within the first day of life due to failure to feed. Heterozygous Tor1a^ΔE/+ mice are viable and do not display abnormal movements, nor any neuropathological abnormalities when analyzed using standard histopathological methods.

Detailed morphometric studies suggest that medium spiny striatal neurons show fewer and thinner dendrites, and electron microscopy indicates a reduction in the ration of ado-spinous to axo-dendritic inputs to striatum.

This line can be used in conjunction with mice carrying a floxed Tor1a allele (Stock No. 025832) and B6.Cg-Tg(Nes-cre)1Kln/J mice (Stock No. 003771) to generate the first viable model of primary dystonia with overt twisting movements similar to those seen in the human disease; these animals also exhibit selective areas of neurodegeneration in discrete sensorimotor structures. To generate such nestin selective knock-in mice ("N-SKI"), Stock Nos. 025832 and 003771 are first intercrossed to generate animals with one floxed Tor1a allele and the nestin-Cre transgene. These animals are subsequently crossed to this line carrying the ΔE allele (Stock No. 25637) to yield N-SKI Tor1aflox/ΔE Cre+ animals.

Development

A targeting construct was made to create a pathogenic glutamic acid residue deletion in exon 5 of the torsin family 1, member A (torsin A) (Tor1a) gene, resulting in the ΔE knockin shown to cause the autosomal dominant disorder, DYT1 dystonia. The targeting vector also contained a loxP-flanked neo cassette upstream of exon 5. The construct was electroporated into 129S1/Sv-Oca2⁺ Tyr⁺ Kitl⁺-derived W9.5 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts and resulting chimeric mice were bred to 129SvEv/Tac mice. Offspring were bred with Hs-cre6 transgenic mice to delete the neo cassette, and progeny were crossed to remove the Cre-expressing transgene. These Tor1a^ΔE mice were maintained on a mixed background. Upon arrival, mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish the colony.

Control Suggestions

Wild-type from the colony

Additional Information

Considerations for Choosing Controls

Selected References

Goodchild RE; Kim CE; Dauer WT. 2005. Loss of the dystonia-associated protein torsinA selectively disrupts the neuronal nuclear envelope. Neuron 48(6):923-32PubMed: 16364897 MGI: J:107596

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Genetics

Tor1a^tm2Wtd

Allele Symbol: Tor1a^tm2Wtd

Allele Name	targeted mutation 2, William T Dauer
Allele Type	Targeted (Hypomorph)
Allele Synonym(s)	DYT1 KI; DYT1(deltaE); Tor1a^deltaE; Tor1a^deltagag
Gene Symbol and Name	Tor1a, torsin family 1, member A (torsin A)
Gene Synonym(s)
Strain of Origin	129S1/Sv-Oca2⁺ Tyr⁺ Kitl⁺
Chromosome	2
Molecular Note	A targeting vector was designed to create a pathogenic glutamic acid deletion in exon 5. A neomycin resistance gene included in the vector was subsequently removed via cre mediated recombination.

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).

torsion dystonia 1

Research Areas By Phenotype

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

Neurobiology Research
- Receptor Defects
  - dopamine receptor
- Channel and Transporter Defects
  - calcium: glutamate receptor
- Cerebellar Defects
- Ataxia (Movement) Defects
Developmental Biology Research
- Postnatal Lethality
  - Homozygous

Mammalian Phenotype Terms by Genotype

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

Genotype: Tor1a^tm2Wtd/Tor1a^tm2Wtd
involves: 129S1/Sv

behavior/neurological phenotype

abnormal suckling behavior
- homozygous pups fail to feed after birth

decreased vocalization
- homozygous pups do not vocalize after birth

cellular phenotype

abnormal cell nucleus morphology
- E18.5 mutants exhibit nuclear envelope bleb formation in the cortex (7%), striatum (1.2%), and cerebellum (81%)
- lumen of the nuclear envelope contains large numbers of vesicles that appear to derive from the inner nuclear membrane; ventral horn neurons are most affected

mortality/aging

neonatal lethality, complete penetrance
- homozygotes typically die within 48 hours after birth
- Background Sensitivity - median survival is 1.5 days, longer than on a mixed 129S1/Sv and C57BL/6 background but shorter than on a mixed 129S1/Sv/CD-1/ICR or mixed 129S1/Sv and DBA/2J background

nervous system phenotype

abnormal neuron physiology
- hippocampal neurons exhibit an accelerated cytoplasmic calcium concentration decay compared to controls
- treatment with glutamate-receptor antagonist does not affect the accelerated decay seen in neurons

Genotype: Tor1a^tm2Wtd/Tor1a⁺
involves: 129S1/Sv

cellular phenotype

abnormal cell nucleus morphology
- nuclear envelope is normal compared to homozygous Tor1a homozygous or compound mutants

mammalian phenotype

behavior/neurological phenotype
- Normal - males have no apparent behavioral abnormalities

nervous system phenotype

abnormal neuron physiology
- hippocampal neurons exhibit a prolonged cytoplasmic calcium concentration decay, indicating that neurons experience calcium overload
- treatment with glutamate-receptor antagonist results in the ablation of this prolonged decay

Genotype: Tor1a^tm1Wtd/Tor1a^tm2Wtd
involves: 129S1/Sv

cellular phenotype

abnormal cell nucleus morphology
- lumen of the nuclear envelope contains large numbers of vesicles that appear to derive from the inner nuclear membrane

Genotype: Tor1a^tm2Wtd/Tor1a⁺
B6.129S1-Tor1a

mammalian phenotype

behavior/neurological phenotype
- Normal - males do not display altered responses to drug challenge
- Normal - males exhibit normal motor activity in the open field and habituate similar to wild-type males, normal rotarod behavior and similar performance to wild-type on the beam-walking test

nervous system phenotype

abnormal brain white matter morphology
- abnormal white matter microstructure, showing a reduction in fractional anisotropy, a magnetic resonance diffusion tensor imaging index of axonal integrity and coherence
- white matter abnormalities are localized to the right superior cerebellar tract, the white matter subjacent to the right primary sensorimotor cortex, and the left caudate/putamen

abnormal cerebellum vermis morphology
- FDG microPET indicates a single brain region with abnormal glucose utilization localized to the superior cerebellar vermis, with increased local metabolic activity

abnormal dorsal striatum morphology
- fractional anisotropy reduction in the caudate/putamen

abnormal nervous system tract morphology
- fewer tracts, with fiber count reductions, in the rostral (-59%) and caudal (-86%) pontocerebellar pathways
- reduction of tract numbers in cerebellothalamic (-49%), thalamocortical (-55%) and thalamostriatal (-86%) projection pathways

abnormal Purkinje cell dendrite morphology
- dendritic spines in Purkinje cells appear thinner and less complex, showing a 14% lower spine density in mutants and 5% lower spine density in females compared to males
- Purkinje cells show subtle abnormalities among the dendritic trees, showing fewer dendrites and shorter total dendritic lengths

ectopic Purkinje cell
- heterotopic Purkinje cells are more frequent in the caudal cerebellum compared to the anterior cerebellum
- mutants exhibit 33% more heterotopic Purkinje cells in the cerebellum than controls

enlarged cerebellum
- Normal - however, no structural abnormality of deep cerebellar nuclei neurons or Purkinje cell numbers
- subtle enlargement of the cerebellum, with total volume of the cerebellum including granule cell layer, molecular cell layer, and deep cerebellar nuclei is slightly increased

Genotype: Tor1a^tm2Wtd/Tor1a^tm2Wtd
involves: 129S1/Sv * C57BL/6J

mortality/aging

neonatal lethality, complete penetrance
- Background Sensitivity - median lifespan is 0.5 days, shorter than on a 129S1/Sv background or other backgrounds studied

Genotype: Tor1a^tm2Wtd/Tor1a^tm2Wtd
involves: 129S1/Sv * DBA/2J

behavior/neurological phenotype

abnormal eating behavior
- pups do not feed well and appear generally ill

abnormal gait
- mutants that live through the end of the first postnatal week develop abnormal motor behavior, showing tremor and prolonged twisting movements gait, particularly of the hindlimbs

tremors
- mutants that live through the end of the first postnatal week develop abnormal motor behavior, showing tremor and prolonged twisting movements gait, particularly of the hindlimbs

mortality/aging

postnatal lethality, complete penetrance
- Background Sensitivity - median survival is 3.5 days, although survival up to 21 days is seen and 13.2% live longer than 7 days; survival is longer than any of the other backgrounds studied, including on the 129S1/Sv or a mixed 129S1/Sv and C57BL/6J background

Genotype: Tor1a^tm2Wtd/Tor1a^tm2Wtd
D2.129S1-Tor1a

cellular phenotype

abnormal cell nucleus morphology
- E18.5 mutants exhibit nuclear envelope bleb formation in the cortex (8%), striatum (6%), and cerebellum (71%)

mortality/aging

postnatal lethality, complete penetrance
- Background Sensitivity - median survival is 1.5 days, similiar to survival on the 129S1/Sv background but longer than on a mixed 129S1/Sv and C57BL/6J background and shorter than on mixed 129S1/Sv/CD-1/ICR and mixed 129S1/Sv/DBA/2J backgrounds

Genotype: Tor1a^tm2Wtd/Tor1a^tm2Wtd
involves: 129S1/Sv * CD-1

mortality/aging

postnatal lethality, complete penetrance
- Background Sensitivity - median lifespan is 2.5 days and all mutants die by P3.5; survival is longer than on the 129S1/Sv or mixed 129S1/Sv and C57BL/6 background

Genotype: Tor1a^tm2Wtd/Tor1a^tm4.2Wtd
involves: 129S/SvEv * 129S1/Sv * C57BL/6

behavior/neurological phenotype

abnormal reflex
- sustained forepaw straining during tail suspension
- truncal twisting during tail suspension

decreased grip strength
- impaired ability to remain suspended in horizontal grid hang test (decreased latency to fall)

hunched posture
- hunched posture on balance beam

impaired balance
- balance beam crossing using forepaws and dragging hind paws
- increased number of footslips on balance beam as compared to control

impaired coordination
- balance beam crossing using forepaws and dragging hind paws
- increased number of footslips on balance beam as compared to control

limb grasping
- forelimb clasping during tail suspension

tremors

weakness

growth/size/body region phenotype

decreased body weight
- reduced body weight beginning at P7 as compared to controls

mortality/aging

premature death
- 47.37% survival rate
- most of loss occurs by 30 days of age

nervous system phenotype

abnormal cerebellum deep nucleus morphology
- reduced numbers of deep cerebellar nuclei

abnormal neuron morphology
- ubiquitin accumulation found in deep cerebellar nuclei, cortex, thalamus, red nucleus and facial motor nucleus

gliosis
- regions of gliosis found in deep cerebellar nuclei, cortex, thalamus, red nucleus and facial motor nucleus

neurodegeneration

vision/eye phenotype

delayed eyelid opening

References

Goodchild RE; Kim CE; Dauer WT. 2005. Loss of the dystonia-associated protein torsinA selectively disrupts the neuronal nuclear envelope. Neuron 48(6):923-32PubMed: 16364897 MGI: J:107596

Additional - Tor1a^tm2Wtd related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Sanger sequencing:Tor1a
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, heterozygous mice may be bred to wildtype mice from the colony. On a C57BL/6 background, homozygous animals die within the first day of life due to failure to feed.
- Additional Breeding and Husbandry Support
Citation
When using the STOCK Tor1a^tm2Wtd/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #025637 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 Tor1a<tm2Wtd>

Related Products and Services

Frozen Mouse Embryo	STOCK Tor1a<tm2Wtd>/J Frozen Embryo	$2595.00
Frozen Mouse Embryo	STOCK Tor1a<tm2Wtd>/J Frozen Embryo	$2595.00
Frozen Mouse Embryo	STOCK Tor1a<tm2Wtd>/J Frozen Embryo	$3373.50
Frozen Mouse Embryo	STOCK Tor1a<tm2Wtd>/J Frozen Embryo	$3373.50

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Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Tor1atm2Wtd

Allele Symbol: Tor1atm2Wtd

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: Tor1atm2Wtd/Tor1atm2Wtdinvolves: 129S1/Sv

behavior/neurological phenotype

cellular phenotype

mortality/aging

nervous system phenotype

Genotype: Tor1atm2Wtd/Tor1a+involves: 129S1/Sv

cellular phenotype

mammalian phenotype

nervous system phenotype

Genotype: Tor1atm1Wtd/Tor1atm2Wtdinvolves: 129S1/Sv

cellular phenotype

Genotype: Tor1atm2Wtd/Tor1a+B6.129S1-Tor1a

mammalian phenotype

nervous system phenotype

Genotype: Tor1atm2Wtd/Tor1atm2Wtdinvolves: 129S1/Sv * C57BL/6J

mortality/aging

Genotype: Tor1atm2Wtd/Tor1atm2Wtdinvolves: 129S1/Sv * DBA/2J

behavior/neurological phenotype

mortality/aging

Genotype: Tor1atm2Wtd/Tor1atm2WtdD2.129S1-Tor1a

cellular phenotype

mortality/aging

Genotype: Tor1atm2Wtd/Tor1atm2Wtdinvolves: 129S1/Sv * CD-1

mortality/aging

Genotype: Tor1atm2Wtd/Tor1atm4.2Wtdinvolves: 129S/SvEv * 129S1/Sv * C57BL/6

behavior/neurological phenotype

growth/size/body region phenotype

mortality/aging

nervous system phenotype

vision/eye phenotype

References

Additional - Tor1atm2Wtd 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

Related Products and Services

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

Tor1a^tm2Wtd

Allele Symbol: Tor1a^tm2Wtd

Genotype: Tor1a^tm2Wtd/Tor1a^tm2Wtd
involves: 129S1/Sv

Genotype: Tor1a^tm2Wtd/Tor1a⁺
involves: 129S1/Sv

Genotype: Tor1a^tm1Wtd/Tor1a^tm2Wtd
involves: 129S1/Sv

Genotype: Tor1a^tm2Wtd/Tor1a⁺
B6.129S1-Tor1a

Genotype: Tor1a^tm2Wtd/Tor1a^tm2Wtd
involves: 129S1/Sv * C57BL/6J

Genotype: Tor1a^tm2Wtd/Tor1a^tm2Wtd
involves: 129S1/Sv * DBA/2J

Genotype: Tor1a^tm2Wtd/Tor1a^tm2Wtd
D2.129S1-Tor1a

Genotype: Tor1a^tm2Wtd/Tor1a^tm2Wtd
involves: 129S1/Sv * CD-1

Genotype: Tor1a^tm2Wtd/Tor1a^tm4.2Wtd
involves: 129S/SvEv * 129S1/Sv * C57BL/6

Additional - Tor1a^tm2Wtd related