Galctwi
Spontaneous Allele Detail
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| Nomenclature |
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Symbol:
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Galctwi
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Name:
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galactosylceramidase;
twitcher
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MGI ID: |
MGI:1856218 |
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Synonyms: |
galc-, twi |
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Gene:
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Galc
Location:
Chr12:99440510-99497547 bp, - strand
Genetic Position: Chr12,
48.0 cM
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Mutation
origin |
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Mutation
description |
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Allele
Type: |
Spontaneous |
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Mutation: |
Single point mutation |
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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. (J:31433) |
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Inheritance: |
Recessive |
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| Find Mice (IMSR) |
Mouse strains and cell lines available from the
International Mouse Strain Resource
(IMSR)
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Phenotype
summary
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Phenotype Summary by Mammalian Phenotype terms
(show or
hide all annotated terms)
Genotypes are listed in the next section.
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Key:
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| hm |
homozygous |
ht |
heterozygous |
| cn |
conditional genotype |
cx |
complex: > 1 genome feature |
| tg |
involves transgenes |
ot |
other: hemizygous, indeterminate,... |
| N |
normal phenotype |
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expected model not found |
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Phenotypic
data by
genotype
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Phenotypic Data by Genotype
(show or
hide all phenotypic details)
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Disease
models
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Notes |
The principal pathological changes are degeneration of myelin sheaths in both the central and peripheral nervous systems, presence of multinucleated macrophages (globoid cells) containing a variety of inclusions in which there are crystalline and multi-angular structures and twisted tubules (J:6390), and endoneurial edema (J:7115). These abnormalities closely resemble those of human globoid cell leukodystrophy (Krabbe's disease) (J:6390).
In the brain and liver of twitcher homozygotes, there is a profound deficiency of galactosylceramidase and lactosylceramidase activity. Heterozygotes have intermediate levels of both enzymes. Twitcher is thus a model enzymatically, as well as morphologically and clinically, of Krabbe's disease (J:6423). Human Krabbe's disease cell/mouse twitcher cell hybrids show no complementation for the missing enzyme (J:35073).
In the central nervous system oligodendrocytes (J:31433), and in the peripheral nervous system Schwann cells (J:6477), form myelin. Dysfunction and degeneration of these cells in twitcher mice leads to the loss of myelination characteristic of the gene defect. The defect was shown to be intrinsic to the Schwann cells in peripheral nerve by means of nerve-grafting experiments (J:6477). When sciatic nerves from affected mice were grafted into trembler (Pmp22/+) mice, which have defective Schwann cells, 1 to 4 months after grafting they showed normal myelin, no globoid cells, and very little endoneurial edema (J:6749). Grafting to normal hosts also results in increased galactosylceramidase activity, presumably due to enzyme replacement in the mutant Schwann cells (J:7223). Proliferative capacity of Schwann cells was shown to be reduced in Galctwi/Galctwi homozygotes, even before demyelination becomes evident (J:3584).
Transplantation of normal hematopoietic cells into twitcher mice gradually repairs the demyelination of the peripheral nerves, probably by enzyme transfer from normal macrophages (J:7576). When wild-type fetal liver cells, as a source of normal hematopoietic tissue, and fetal brain cells, as a source of normal oligodendrocytes, are transplanted together into twitcher mice, the increase in survival time is greater than with hematopoietic cells alone, and transplanted oligodendrocytes disseminate throughout the central nervous system (J:1327). Native oligodendrocytes are capable of proliferating within the twitcher spinal cord, but total numbers decline because degeneration exceeds proliferation (J:23073).
In spite of the deficiency of enzyme in affected mice and in patients with Krabbe's disease, there is no accumulation of the normal substrate, galactosylceramide, in the nervous system. However, in twitcher mice, beginning at 7 days old, there is a rapid and progressive accumulation of a toxic metabolite, psychosine (galactosylsphingosine), which is also a substrate for galactosylceramidase. No psychosine was detected in either homozygous normal or heterozygous mice. The accumulation of psychosine is thought to be responsible for death of myelin-forming cells and demyelination in affected mice and probably also in patients with Krabbe's disease (J:7427).
Globoid cells characteristic of neural tissue in twitcher mice are microglia/macrophages engorged with cell debris and galactosylceramide (J:3948). A subset of these cells express class II major histocompatibility complex molecules (H2-A and H2-E) (J:2124). This expression may be a local reaction to degenerating tissue components; on the other hand, it may represent pathogenic involvement of immunological responses in cell degeneration (J:15111). A reduction in central nervous system demyelination, infiltration of microglia or macrophages, and twitching in twitcher mice with a null mutation for H2-Ab1 suggests a possible causative role (J:19914).
In the kidneys of twitcher mice, in contrast to the nervous system, there is a large increase of galactosylceramide (50x normal), with a smaller increase in liver and lung (J:7311). This is accompanied by presence in the loop of Henle of the kidneys of large numbers of inclusions of the type found in the globoid cells of the nervous system (J:7313).
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| References |
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Original: |
J:13867
Duchen LW,
"A new neurological mutant "twitcher" (twi)"
Mouse News Lett 1979;61():47
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All: |
54 reference(s)
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