Tor1aΔE mice contain a pathogenic glutamic acid residue deletion in the Tor1a gene, making this stain useful for studying DYT1 dystonia.
William Dauer, University of Michigan Medical School
Tor1aΔE 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 Tor1aΔE/+ 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.
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 Tor1aΔE 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.
|Allele Name||targeted mutation 2, William T Dauer|
|Allele Type||Targeted (Hypomorph)|
|Allele Synonym(s)||Tor1atm2Wtd; targeted mutation 2, William T Dauer|
|Gene Symbol and Name||Tor1a, torsin family 1, member A (torsin A)|
|Gene Synonym(s)||DQ2; dystonia 1; Dyt1; DYT1; torsinA; torsin family 1, member A; Dyt1|
|Strain of Origin||129S1/Sv-Oca2+ Tyr+ Kitl+|
|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.|
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.
When using the STOCK Tor1atm2Wtd/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #025637 in your Materials and Methods section.
|Heterozygous or wildtype for Tor1a<tm2Wtd>|
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