Heterozygous mice carrying a 266 CAG repeat knock-in from the human ataxin 7 gene exhibit hypoactivity, progressive weight loss, retarded growth after 5 weeks of age, droopy eyelids (ptosis) and receded eyes, visual impairment, ataxia, muscle wasting, curvature of the spine (kyphosis), and tremors which are triggered whenever they initiate movement. Some mice developed myoclonic seizures around 12 weeks of age. Homozygous mice show a gene dosage effect, with their phenotype being more severe and disease progression more rapid, resulting in death around 7-8 weeks of age. These mice may be useful as a model of spinocerebellar ataxia type 7 (SCA7).
Huda Zoghbi, Baylor College of Medicine
Heterozygous mice carrying a 266 CAG repeat knock-in from the human ataxin 7 gene exhibit hypoactivity, progressive weight loss, retarded growth after 5 weeks of age, droopy eyelids (ptosis) and receded eyes, visual impairment, ataxia, muscle wasting, curvature of the spine (kyphosis), and tremors which are triggered whenever they initiate movement. At the terminal stage of the disease, animals became extremely hypokinetic and did not drink nor eat, even when their chow was wetted and placed at the bottom of the cage. Some mice developed myoclonic seizures around 12 weeks of age and many of the heterozygotes die around this age. Homozygous mice show a gene dosage effect, with their phenotype being more severe and disease progression more rapid, resulting in death around 7-8 weeks of age. The heterozygous mice develop retinal degeneration and post-tetanic potentiation (PTP) impairment. The knock-in expression pattern matches that of wildtype mice in the cerebellum, retina, hippocampus and other brain regions with accumulation of the expanded CAG in these tissues. These mice may be useful as a model of spinocerebellar ataxia type 7 (SCA7).
A targeting vector containing 266 CAG repeats amplified from a human patient's gene was used to create a knock-in of mouse exon 3. A selectable cassette containing the neomycin resistance and thymidine kinase genes flanked by two loxP sites was inserted about 2.3 kb downstream of mouse exon 4. The vector was introduced to 129S7/SvEvBrd-Hprt1+-derived AB2.2 embryonic stem (ES) cells. Subsequent electroporation of Cre recombinase into positive ES cell clones excised the floxed fragment. Chimeras were crossed to C57BL/6J for more than ten generations by the donating laboratory. This is line H10.
|Allele Name||targeted mutation 1, Huda Y Zoghbi|
|Allele Synonym(s)||Sca7266Q/5Q; Sca7266Q|
|Gene Symbol and Name||Atxn7, ataxin 7|
|Promoter||Atxn7, ataxin 7, mouse, laboratory|
|Strain of Origin||129S7/SvEvBrd-Hprtb-m2|
|Molecular Note||The polyglutamine tract in exon 3 was expanded to 266 CAG repeats via homologous recombination. A single loxP site remained downstream of exon 4. While levels of mutant and wild-type transcript were similar in heterozygous mutant mice, immunostaining of brain tissue indicated increased levels mutant protein. The number of CAG repeats did not decrease by more than 10 (30 nt) in the two lines initially studied. Naturallly occurring contracted mutations of the 266Q tract have been observed, resulting in 230 and 100 CAG repeats.|
|Mutations Made By|| |
Huda Zoghbi, Baylor College of Medicine
When maintained as a live colony, heterozygotes may be bred. Male heterozygous mice are reported to have reduced fertility after 8 weeks of age. Female heterozygous mice are said to fail to deliver pups when they are mated after 8 weeks of age.
When using the B6.129S7-Atxn7tm1Hzo/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #008682 in your Materials and Methods section.
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