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Phenotypes Associated with This Genotype
Genotype
MGI:8235453
Allelic
Composition
Tg(Gfap-cre)73.12Mvs/0
Twnktm1.1Suom/Twnktm1.1Suom
Genetic
Background
involves: BALB/c * C57BL/6NHsd * C57BL/6JOlaHsd
Find Mice Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Tg(Gfap-cre)73.12Mvs mutation (2 available)
Twnktm1.1Suom mutation (0 available); any Twnk mutation (27 available)
phenotype observed in females
phenotype observed in males
N normal phenotype
mortality/aging
• mice treated with the mTORC1 inhibitor rapamycin at 1.5 months of age start to lose weight after only 2 weeks of age and reach humane end point at 2.3 months of age
• mice treated with rapamycin starting at 3 months of age show weight loss at already the third day of treatment and reach human end point 2 weeks after treatment initiation
• mice reach humane end point by 5-6 months of age
• mice fed a ketogenic diet after weaning before disease manifestation reach humane end point after 9.5 weeks of treatment

growth/size/body
• mice show progressive weight loss starting from 2-3 months of age
• mice treated with the mTORC1 inhibitor rapamycin at 1.5 months of age start to lose weight after only 2 weeks of age and mice treated with rapamycin starting at 3 months of age show weight loss at already the third day of treatment

homeostasis/metabolism
• saccharopine, the degradation produce of lysine, is the most significantly increased metabolite
• rapamycin treatment partially rescues the saccaropine increase
• the level of sacccharopine is further increased in ketogenic diet-fed mice
• aspartate levels are reduced in the brain
• aspartate, produced in the mitochondria, is decreased in ketogenic diet-fed mice
• 3.6-fold increase of glycine in the brain
• the elevated glycine level is normalized by rapamycin treatment
• level of glycine is further increased in ketogenic diet-fed mice
• increase in proline levels in the brain
• 4.5- and 3.6-fold increase of serine and glycine in the brain, indicating induction of de novo serine biosynthesis
• the elevated serine level is normalized by rapamycin treatment
• level of serine is further increased in ketogenic diet-fed mice, despite de novo serine synthesis enzyme expression levels not being detected
• mice show increased expression of transsulfuration enzymes
• expression of transsulfuration enzymes is increased in ketogenic diet-fed mice
• several lipid metabolites are slightly decreased in the brain
• rapamycin has no effect on lipid metabolites in the brain
• several purine precursors or degradation products are increased in the brain
• uracil, a pyrimidine metabolite, is increased in the brain
• ATP, ADP, UDP, and FAD decline in ketogenic diet-fed mutant mice but not in controls, indicating an imbalance of nucleotide metabolism and high-energy phosphate donors
• mice treated with the mTORC1 inhibitor rapamycin at 1.5 months of age start to lose weight after only 2 weeks of age and reach humane end point at 2.3 months of age
• mice treated with rapamycin starting at 3 months of age show weight loss at already the third day of treatment and reach human end point 2 weeks after treatment initiation
• treatment with rapamycin exacerbates spongiosis, gliosis and mitochondrial integrated stress response in the brain
• rapamycin treatment increases methionine levels and glutamine levels, suggesting either increased production or decreased usage

nervous system
• progression of reactive gliosis is unaffected by rapamycin
• mice fed a ketogenic diet after weaning before disease manifestation show more severe gliosis than in mice fed a chow diet
• 2.3-month-old mice show sparsely located holes in the brain parenchyma
• rapamycin treatment started at 1.5 months or 3 months of age does not improve but increases progression of mitochondrial spongiotic encephalopathy
• mice fed a ketogenic diet after weaning before disease manifestation, show worsening of brain pathology, with more severe spongiosis and gliosis than in mice fed a chow diet

cellular
• progression of reactive gliosis is unaffected by rapamycin
• mice fed a ketogenic diet after weaning before disease manifestation show more severe gliosis than in mice fed a chow diet
• mitochondrial integrated stress response, as indicated by activation of related genes, is induced in the brain of 5.5-month-old mice but not in 2.3-month-old mice
• mice fed a ketogenic diet show further induction of the mitochondrial integrated stress response

Mouse Models of Human Disease
DO ID OMIM ID(s) Ref(s)
mitochondrial DNA depletion syndrome DOID:0070329 OMIM:PS603041
J:304258


Contributing Projects:
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO)
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last database update
07/29/2025
MGI 6.24
The Jackson Laboratory