The first outward sign of homozygosity for the recessive mutation Usp14ax-J is an unsteady gait, particularly in the hind quarters, that can be detected by approximately 2 weeks of age. These pups often show difficulty in righting themselves when turned on their backs. They have a rapid tremor that is most apparent when they are active. Extensor paralysis progresses and wasting of the hind quarters ensues until the hind quarters are not functional and the mouse can not sit upright or move except through the use of onlyits front limbs. Although death is premature, viability in the first two to three weeks is not diminished. At 18 days of age these mutants weigh an average of 15% less than wildtype controls and by 45 days this difference is increased such that they weigh 50-60% less than wildtype controls. Homozygotes do not breed. The lumbar vertebrae are slightly shorter than normal with shorter spinous processes and more elongate foramen. These homozygotes have defects in synaptic transmission in the central and peripheral nervous systems. End plate potentials are altered at neuromuscular junctions. D'Amato et al. published an extensive histological assessment of the Usp14ax-J/Usp14ax-J brain in which they reported that the corpus collosum, cingulum, and hippocampal commissureare underdeveloped as are particular nuclei and long tracts of the brain stem. The pons is shorter longitudinally and deficiencies are also found in the trapezoid body, as well as spinal nerves and spinal cord white matter. The medial lemniscus is smaller than normal only from the ventral beginning in the medulla to an area rostral to the substantia nigra and cerebral peduncles (for more detail see D'Amato et al., 1965.). A.M. Burt described abnormalities in the differentiation of the dendritic trees of CA1 pyramidal cells of the hippocampus and granule cells of the dentate gyrus. This is consistent with altered developmental apoptosis. Ohgoh et al. subsequently found significant apoptosis in the granule cell layer of the cerebellum but not the dentate gyrus or olfactory bulb. Ohgoh et al. also found no TUNEL staining of Purkinje cells, but the early report by D'Amato et al. identified disordered development and degenerative deformities of Purkinje cells. (Lyon, 1955; D'Amato and Hicks, 1965; Burt, 1980; Ohgoh et al., 2000; Wilson et al., 2002.)
The mutation ataxia, Usp14ax, arose spontaneously in 1950 in CBA/H at Edinburgh, Scotland in the control series of a gamma ray mutagenesis experiment. In 1952 the kreisler mutation (Mafbkr) in a multiple recessive stock was imported into The Jackson Laboratory from Dr. Mary Lyon then at Edinburgh. This pair was mated and a female offspring was then mated back to the imported father and produced two ataxic type offspring. This newly identified mutation was called "paralytic" and was maintained by test matings within stock. In 1961 heterozygotes for "paralytic" were sent to Dr. Mary Lyon for allele testing with ataxia because of the similar phenotype. The test was positive and the "paralytic" mutation was then re-named ataxia Jackson (Usp14ax-J). In 1999 the possibility of ataxia Jackson being the same as the original ataxia was considered, and Dr. Lyon was asked to check the original pairs of kreisler mice for the presence of ataxia. She found that the imported male (#SU71.175) was homozygous for kreisler and heterozygous for ataxia (Usp14ax), having come from an ataxic mother, and the imported female (#SU88.197) was heterozygous for kreisler and a possible carrier of ataxia. Therefore, Usp14ax-J is probably the same mutation as the original Usp14ax.
This strain is congenic. In 1959 a "paralytic&" (ataxia Jackson) carrier female was outcrossed to a C57BL/6J male and backcrossing to C57BL/6J was continued to N6 after which the strain was sibling bred as tested pairs, reaching N6F25 in 1971 as ataxia Jackson stock. In 1971 Dr. Eva Eicher maintained ataxia Jackson by backcrossing to C57BL/6JEi via ovarian transplant using B6CBAF1 hosts. This strain was cryopreserved in 1984 by mating C57BL/6J females with heterozygous congenic males at N18F1.
|Allele Name||ataxia Jackson|
|Allele Type||Spontaneous (Hypomorph)|
|Allele Synonym(s)||ax; axJ; paralytic; pr; Usp14asJ; Usp14axJ|
|Gene Symbol and Name||Usp14, ubiquitin specific peptidase 14|
|Strain of Origin||STOCK Mafbkr|
|General Note||There is sufficient reason to believe that axJand ax represent the same mutation. The kreisler stock was imported to The Jackson Laboratory from Edinburgh in 1952. The axJ mutation arose at The Jackson Laboratory in the kreisler stock in 1953 and was originally called paralytic. Mary Lyon, also in Edinburgh, reported the ataxia mutation shortly thereafter. Paralytic heterozygotes were sent to Mary Lyon and found to be allelic with her ataxia mutant. Thus the name was changed from paralytic to ataxia. The Jackson Laboratory investigated the possibility that ax and axJ were really the same strain. Examination of the original shipping records and pedigree numbers showed that the original kreisler male and female mice shipped to the laboratory in 1952, were potentially heterozygote for the ax mutation (J:58683).|
|Molecular Note||The mutation underlying this phenotypic mutant has been identified as an IAP insertion into intron 5 of the Usp14 gene. The insertion results in a number of aberrant splice products containing stop codons immediately following the splice junction. Low levels of wild-type transcript are observed in homozygous mutant animals, suggesting that this allele is hypomorphic.|
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