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Allele Symbol Allele Name Allele ID |
Epm2atm1Kzy targeted mutation 1, Kazuhiro Yamakawa MGI:2182627 |
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| Summary |
3 genotypes
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• Lafora bodies are non-membrane bound in the sarcoplasm of myocytes in the myocardium and skeletal muscle
• Lafora bodies are smaller than in Epm2btm1.1Geno homozygotes
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• at 4 months, homozygotes exhibit a deficit in retention in the passive avoidance task
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• mutants exhibit an increase in water intake
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• mutants exhibit an increase in food intake compared to controls
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• at 4 months, homozygotes display an increased magnitude of acoustic startle reflex in response to a stimulus of standard intensity
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• at 9 months, homozygotes display impaired balance
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• at 9 months, homozygotes display impaired coordination
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• at 9 months, homozygotes display a significantly reduced grip strength relative to wild-type
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• at 9 months, homozygotes develop spontaneous myoclonic seizures (~80% penetrance)
• at this age, homozygotes exhibit ear and head spasms and shoulder jerks or minor shaking of the torso
• each episode lasts for a few seconds and comprises of 1-2 jerks
• homozygotes only develop spike and slow-wave formations as opposed to regular and well-formed EEG difuse 3-6 Hz spike-wave complexes
• homozygotes do NOT develop grand mal tonic-clonic seizures up until 1 year of age
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• at 9 months, homozygotes develop spontaneous myoclonic seizures (~80% penetrance)
• at this age, homozygotes exhibit ear and head spasms and shoulder jerks or minor shaking of the torso
• each episode lasts for a few seconds and comprises of 1-2 jerks
• homozygotes only develop spike and slow-wave formations as opposed to regular and well-formed EEG difuse 3-6 Hz spike-wave complexes
• homozygotes do NOT develop grand mal tonic-clonic seizures up until 1 year of age
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• mutants treated with insulin exhibit an accumulation of glycogen in cardiomyocytes
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• mutants exhibit increased glucose uptake in the heart, resulting in increased glycogen levels and formation of polyglucosan inclusions
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• at 9 months, homozygotes display reduced neuromuscular strength and endurance force in the dynamometer relative to wild-type
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• at 9 months, homozygotes develop spontaneous myoclonic seizures (~80% penetrance)
• at this age, homozygotes exhibit ear and head spasms and shoulder jerks or minor shaking of the torso
• each episode lasts for a few seconds and comprises of 1-2 jerks
• homozygotes only develop spike and slow-wave formations as opposed to regular and well-formed EEG difuse 3-6 Hz spike-wave complexes
• homozygotes do NOT develop grand mal tonic-clonic seizures up until 1 year of age
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• in neurons, mitochondrial, endoplasmic reticulum and Golgi apparatus swelling with lysis of cell membranes results in cell death
• neuronal cell death and Lafora inclusion bodies precede the behavioral deficits, ataxia, and myoclonic epileptiform activity
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• at 2 months, hippocampal pyramidal and granular cells, and cerebral cortical pyramidal cells exhibit signs of degeneration, such as dark mitochondria, enlarged cisterni of endoplasmic reticulum, and a collapsed Golgi apparatus
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• at 2 months, cerebellar Purkinje cells show signs of degeneration, including a shrunken cytoplasm with enlarged cisterni, abnormally dense mitochondria, lipofuscin granules and an invaginated nucleus
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• at 2 months, homozygotes display a few small PAS+ inclusions (Lafora bodies) within neurons throughout the brain
(J:76688)
• by 4 months, prominent PAS+ granules are noted in the hippocampus, cerebellum, cerebral cortex, thalamus and brain stem
(J:76688)
• in these brain regions, Lafora inclusion bodies are positive for ubiquitin and advanced glycation end-products (AGEP)
(J:76688)
• by 9 months, large Lafora inclusions in the neuronal cytoplasm often displace the nucleus and other organelles
(J:76688)
• at 9 months, Lafora bodies are also detected in mutant muscle and liver tissues; however, such bodies are not detectable at 4 months, and fail to react with anti-ubiquitin or anti-AGEP antibodies
(J:76688)
• mutants treated with insulin exhibit periodic acid-Schiff-positive inclusions in cardiomyocytes, characteristic of polyglucosan depositions or Lafora bodies
(J:173769)
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• at 2 months, myelinated axons display a disrupted myelin sheath, a watery axoplasm and a central dark body with a granular and a dense component; swollen mitochondria lacking recognizable cristae are obseved
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• homozygotes only develop spike and slow-wave formations as opposed to regular and well-formed EEG difuse 3-6 Hz spike-wave complexes
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• mutants exhibit higher adiposity
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• mutants treated with insulin exhibit an accumulation of glycogen in cardiomyocytes
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• mutants treated with insulin exhibit periodic acid-Schiff-positive inclusions in cardiomyocytes, characteristic of polyglucosan depositions or Lafora bodies
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• mutants exhibit increased glucose uptake in the heart, resulting in increased glycogen levels and formation of polyglucosan inclusions
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• mutants exhibit higher adiposity
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• mutants fed a regular chow diet exhibit an increase in body weight starting at 9 weeks of age
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• mutants treated with insulin exhibit an accumulation of glycogen in cardiomyocytes
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• mutants exhibit lower basal levels of blood glucose, with a much larger difference when mice are fasted for 12 hours, however, plasma insulin levels and liver glycogen levels are no different from controls
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• increase in plasma cholesterol levels, in both the fed state and after 12 hours of starvation
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• increase in plasma levels of non-sterified fatty acids
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• increase in plasma triglyceride levels, in both the fed state and after 12 hours of starvation
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• mutants exhibit an increase in diurnal energy expenditure; this increase in energy expenditure is not explained by an increase in total spontaneous locomotor activity, which is similar to controls, although diurnal and nocturnal distribution of the ambulation is different
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• increase in the enzymes, fatty acid synthase and acetyl-CoA carboxylase
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• respiratory exchange rate indicates that during the nocturnal period, mutants and controls use a similar carbohydrate substrate, but during the diurnal phase, mutants show an increase in the respiratory quotient
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• mutants exhibit a blunted response to a glucose tolerance test after a 12 hour fast that is not due to increased insulin levels, indicating enhanced glucose disposal
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• in the insulin tolerance test, mutants exhibit an increased insulin response, showing a marked drop in glucose levels that do not reach basal levels even after 2 hours after insulin injection
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• accumulation of lipid droplets in the liver
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• mutants exhibit increased glucose uptake in the heart, resulting in increased glycogen levels and formation of polyglucosan inclusions
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• in neurons, mitochondrial, endoplasmic reticulum and Golgi apparatus swelling with lysis of cell membranes results in cell death
• neuronal cell death and Lafora inclusion bodies precede the behavioral deficits, ataxia, and myoclonic epileptiform activity
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| Lafora disease | DOID:3534 |
OMIM:254780 |
J:76688 , J:173769 | |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• unlike in Epm2atm1Kzy homozygotes, mice do not exhibit gliosis, neurodegeneration or myoclonus
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• plasma membrane is not quite as taut as in wild-type mice and exhibits rare synaptic contact loss
• however, cells exhibit a full nuclei and cytoplasms, circular plasma membranes, and a full complement of synapses around the cell body
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• decreased Lafora bodies compared with Epm2atm1Kzy homozygotes
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| N |
• unlike in Epm2atm1Kzy homozygotes, glycogen levels in whole brain and skeletal muscle are normal
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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 04/16/2024 MGI 6.23 |
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