The twitcher mouse is a neurological leukodystrophy mutant first observed in 1976 at The Jackson Laboratory. Initially characterized on a mixed C57BL/6J and CE/J background, a neurological phenotype was first observed by day 30 and homozygotes did not survive beyond three months of age. (Duchen LW, et. al., 1980) Subsequent backcrosses to C57BL/6J and the generation of a full congenic (> 10 backcrosses) shortened the time to onset to approximately 21 days with death by 40 days. Head tremors and decreased body weight are initial clinical indicators and mice are generally less active than unaffected littermates. Muscle weakness in the hindlimbs is a promiment feature with the health of the mutants progressively declining until death. There is a significant lack of myelin in the twitcher CNS, along with astrocytic gliosis. The nerves in the PNS are also demyelinated. The mutant CNS and PNS contain multinucleated, periodic acid-Schiff-positive globoid cells. Electron microscopic anal...
The twitcher mouse is a neurological leukodystrophy mutant first observed in 1976 at The Jackson Laboratory. Initially characterized on a mixed C57BL/6J and CE/J background, a neurological phenotype was first observed by day 30 and homozygotes did not survive beyond three months of age. (Duchen LW, et. al., 1980) Subsequent backcrosses to C57BL/6J and the generation of a full congenic (> 10 backcrosses) shortened the time to onset to approximately 21 days with death by 40 days. Head tremors and decreased body weight are initial clinical indicators and mice are generally less active than unaffected littermates. Muscle weakness in the hindlimbs is a promiment feature with the health of the mutants progressively declining until death. There is a significant lack of myelin in the twitcher CNS, along with astrocytic gliosis. The nerves in the PNS are also demyelinated. The mutant CNS and PNS contain multinucleated, periodic acid-Schiff-positive globoid cells. Electron microscopic analysis shows these cells contain paracrystalline inclusions and twisted tubules.
Galactosylceramidase (GALC) is the enzyme responsible for the initial step of galactosylceramide (or galactocerebroside) degradation. Galactocerebroside is one of the most abundant and unique lipid constituents of the myelin sheath and the twitcher mouse is a useful mutant in which to study myelina tion and myelin metabolism. This substrate of the enzyme GALC, however, does not accumulate in tissues of affected mice (or humans). The pathologies are believed to result from the abnormal accumulation of the cytotoxic metabolite galactosylsphingosine (psychosine), another substrate of GALC that inhibits protein kinase C, that causes myelin-forming cells of the CNS and PNS to dysfunction and undergo apoptosis. Levels of myelin protein mRNAs are normal through postnatal day 20 but decline after day 25, corresponding to the observed pathological demyelinating changes. The data indicate that specific gene expression during myelination appears normal initially. Astrogliosis in the CNS is initiated prior to the appearance of myelin pathologies (as early as postnatal 15) and GFAP mRNA is highly upregulated after day 20, presumably as a response to demyelination. Cytokines are believed to play a major role in the inflammatory responses associated with the disease course. TNF-alpha and IL-6 in the CNS appear to be induced by the pathological condition; reactive astrocytes and microglia contribute to the pathogenic course in the CNS of these mutants.(Taniike et al., 1998; Kobayashi et al., 1980; Suzuki and Suzuki, 1995; LeVine and Brown, 1997; Matsushima et al., 1994).
The twitcher mutation (Galctwi) arose spontaneously at The Jackson Laboratory in 1976 in the CE/J strain when that inbred was at generation F69. The mutant subline was sibling bred for 2 generations and then the mutation was moved onto the C57BL/6J background by means of ovarian transplantation cross-intercross breeding. The female host carrying the homozygous mutation was crossed to a C57BL/6J male and the obligate heterozygote offspring were intercrossed to produce more homozygous females for ovarian transplantation. In 1983 C57BL/6J females were bred with heterozygous males at generation +F2N8F1 to generate embryos for cryopreservation.
|Allele Synonym(s)||galc-; twi|
|Gene Symbol and Name||Galc, galactosylceramidase|
|Gene Synonym(s)||2310068B06Rik; 2310068B06Rik; A930008M05Rik; A930008M05Rik; AW212969; AW413532; Gacy; Gacy; RIKEN cDNA 2310068B06 gene; RIKEN cDNA A930008M05 gene; expressed sequence AW212969; expressed sequence AW413532; galactocerebrosidase; twi; twitcher|
|Strain of Origin||CE/J|
|Molecular Note||Sequence analysis comparisons of cDNA from livers of mice homozygous for this allele and +/+ mice showed a G to A transition at codon 339. Northern analysis showed absence of the most abundant mRNA of mouse galactocerebrosidase in mice homozygous for this allele.|
At least two untested males and two untested females (two pairs) will be recovered (eight or more mice is typical).
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