STOCK Tor1a^tm4.1Wtd/J

Stock number: 028099
Product name: Tor1a^swap
Research areas: Neurobiology Research, Research Tools

Description

Tor1a^swap mutant mice possess loxP sites flanking exon 5 of the Tor1a gene, and also contains a downstream mutant exon 5. Removal of the floxed wild type exons allows expression of the mutant exon 5. This strain may be useful for studying the autosomal dominant disorder, DYT1 dystonia.

Detailed description

Tor1a^swap mutant mice possess loxP sites flanking exon 5 of the torsin family 1, member A (torsin A) Tor1a gene. They also contain a downstream mutant exon 5 with a 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. Tor1a^swap mice that are homozygous for this allele are viable and fertile. When bred to mice that express tissue-specific Cre recombinase, resulting offspring will have wildtype exon 5 deleted, and will instead express the ΔE knockin in the cre-expressing tissues.

When mice are generated carrying one Tor1a^swap allele, one Tor1a^flox allele (from Stock No. 025832) and Cre from B6.Cg-Tg(Nes-cre)1Kln/J mice (from Stock No. 003771), they shoe reduced survival and surviving animals show decreased growth rate adn selective degeneration of CNS motor circuits. A similar phenotype is present in homozygous induced- ΔE KI mice with cre from Stock No. 003771. The increased dosage of torsin A in these animals suppresses the lack of function mediated growth deficiency but does not supress motor abnormalities.

 

Development

A targeting vector was designed by Dr. William Dauer (University of Michigan) to insert a loxP site upstream of exon 5 followed by a frt-flanked neomycin resistance (neo) cassette, and a second loxP site downstream of exon 5 of the torsin family 1, member A (torsin A) (Tor1a) gene. A mutant exon 5, with a glutamic acid residue deletion, was inserted downstream of the neo cassette. This results in a ΔE knockin shown to cause the autosomal dominant disorder, DYT1 dystonia. The construct was electroporated into B6/129SvEv embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts and resulting chimeric mice were bred with Flp transgenic mice to delete the neo cassette. Resulting progeny were crossed to remove the Flp-expressing transgene, and Tor1a^swap offspring were maintained on a mixed B6;129 background. Upon arrival, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize C57BL/6J oocytes (Stock No. 000664).

Allele

Symbol: Tor1a^tm4.1Wtd
Name: targeted mutation 4.1, William T Dauer
MGI accession ID: MGI:5693628
Generation method: Targeted
Attributes: Conditional ready (e.g. floxed); No functional change
Synonyms: Tor1a^swap
Marker symbol: Tor1a
Marker name: torsin family 1, member A (torsin A)
Marker synonyms: AMC5; DQ2; DYT1; torsinA
Chromosome: 2
Strain of origin: 129S/SvEv x C57BL/6
Molecular note: A targeting vector was designed to insert a loxP site upstream of exon 5 followed by a FRT-flanked neomycin resistance (neo) cassette, and a second loxP site downstream of exon 5 of the gene. A mutant exon 5, with a glutamic acid residue deletion, was inserted downstream of the neo cassette. Flp-mediated recombination removed the FRT-flanked neo cassette.