Phenotypes associated with this allele

• Allele Symbol: Immt^{Gt(AW0256)Wtsi}
• Allele Name: gene trap AW0256, Wellcome Trust Sanger Institute
• Allele ID: MGI:3857179
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Immt^Gt(AW0256)Wtsi/Immt^Gt(AW0256)Wtsi	involves: 129P2/OlaHsd	MGI:7580846
ht2	Immt^Gt(AW0256)Wtsi/Immt^+	involves: 129P2/OlaHsd	MGI:7580847

Genotype
MGI:7580846

hm1

• Allelic Composition: Immt^{Gt(AW0256)Wtsi}/Immt^{Gt(AW0256)Wtsi}
• Genetic Background: involves: 129P2/OlaHsd

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

mortality/aging

embryonic lethality during organogenesis, complete penetrance ( J:344896 )

• no viable homozygotes are recovered from E10.5 on

embryo

increased embryonic tissue cell apoptosis ( J:344896 )

• embryos exhibit massive apoptosis at E9.5

abnormal embryo morphology ( J:344896 )

• at E9.5, embryos show no clear shape

decreased embryo size ( J:344896 )

• at E7.5, embryos are much smaller than wild-type controls

growth/size/body

decreased embryo size ( J:344896 )

• at E7.5, embryos are much smaller than wild-type controls

cellular

increased embryonic tissue cell apoptosis ( J:344896 )

• embryos exhibit massive apoptosis at E9.5

Genotype
MGI:7580847

ht2

• Allelic Composition: Immt^{Gt(AW0256)Wtsi}/Immt⁺
• Genetic Background: involves: 129P2/OlaHsd

behavior/neurological

impaired spatial learning ( J:344896 )

• in the Morris water maze test, mice show impaired ability to locate the platform after training, as indicated by an increase in distance, latency and mean annulus crossing at 12 months of age

• however, grip strength and velocity are relatively normal

abnormal motor capabilities/coordination/movement ( J:344896 )

• mice exhibit progressive neurological/motor dysfunction as early as 6 months of age

• however, mice are born in normal Mendelian ratios and show no apparent phenotype at birth

impaired coordination ( J:344896 )

• mice show an increase in the time to cross a balance beam and a higher number of hindfeet missteps at 3 and 6 months of age, indicating poor motor balance and coordination

• treatment with antioxidant N-acetylcysteine (NAC) for 1 year restores the time to cross and the number of hindfeet missteps to wild-type values

abnormal gait ( J:344896 )

• mice exhibit gait abnormalities with shorter stride length but increased hind base and matching at 6 and 12 months of age

short stride length ( J:344896 )

nervous system

abnormal neuron mitochondrial morphology ( J:344896 )

• cerebellar neurons exhibit abnormal mitochondrial morphology, with less condensed mitochondria matrix, vacuolation, and partial loss of mitochondrial cristae at 12 months of age

• treatment with antioxidant N-acetylcysteine (NAC) restores mitochondrial ultrastructure in cerebellar neurons

increased neuron apoptosis ( J:344896 )

• following exposure to X-ray irradiation at P7, cerebellar neurons show increased cell apoptosis relative to similarly treated wild-type cells

enlarged lateral ventricles ( J:344896 )

• mice show partial enlargement of the lateral ventricles

decreased hippocampus volume ( J:344896 )

• mice show a significant reduction in hippocampus volume

decreased Purkinje cell number ( J:344896 )

• mice with overt neurologic defects show a significant loss of cerebellar Purkinje cells at 12 months of age

small cerebellum ( J:344896 )

• mice show a trend towards decreased cerebellum volume

neurofibrillary tangles ( J:344896 )

• mice with overt neurologic defects show increased numbers of neurofibrillary tangles in the hippocampus, suggesting neurodegenerative changes

decreased dopaminergic neuron number ( J:344896 )

• mice with overt neurologic defects show a marked reduction of dopaminergic neurons in the substantia nigra

cellular

abnormal mitochondrial crista morphology ( J:344896 )

• cerebellar neurons exhibit partial loss of mitochondrial cristae at 12 months of age

abnormal mitochondrial matrix morphology ( J:344896 )

• cerebellar neurons exhibit less condensed mitochondria matrix at 12 months of age

abnormal muscle fiber mitochondrial morphology ( J:344896 )

• mice exhibit an increased density of mitochondria in muscle with relatively normal mitochondrial structure at 2 and 10 months of age

abnormal neuron mitochondrial morphology ( J:344896 )

• cerebellar neurons exhibit abnormal mitochondrial morphology, with less condensed mitochondria matrix, vacuolation, and partial loss of mitochondrial cristae at 12 months of age

• treatment with antioxidant N-acetylcysteine (NAC) restores mitochondrial ultrastructure in cerebellar neurons

increased cellular sensitivity to X-ray irradiation ( J:344896 )

• following exposure to X-ray irradiation at P7, mice show markedly increased DNA damage response markers (phosphorylated 53BP1 and SMC1 foci formation) in the external granule cell layer (EGL) of proliferating cerebella and increased cell apoptosis in cerebellar neurons relative to similarly treated wild-type controls

increased neuron apoptosis ( J:344896 )

• following exposure to X-ray irradiation at P7, cerebellar neurons show increased cell apoptosis relative to similarly treated wild-type cells

increased cellular glucose import ( J:344896 )

• mice show a significantly higher level of 18F-fluorodeoxyglucose (18F-FDG) uptake in brain, suggesting increased glucose transport in the neurons

abnormal mitochondrial physiology ( J:344896 )

• cerebella neurons show a significant reduction in mitochondrial membrane potentials, suggesting impaired mitochondrial function

• NAC-treated mitochondria from cerebellar neurons exhibit an elevated O2 consumption and mitochondrial membrane potential at 10 months of age

abnormal oxidative phosphorylation ( J:344896 )

• cerebellar neurons exhibit alterations in mitochondrial oxidative phosphorylation complexes in an age-dependent manner

• respiratory control ratio (RCR) measured by mitochondrial state 3 (R3)/state 4 (R4) is significantly lower than in wild-type controls

• however, mtDNA copy number is normal at 2 and 10 months of age

abnormal mitochondrial ATP synthesis coupled electron transport ( J:344896 )

• aging mice exhibit significantly impaired OXPHOS function and ATP generation in brain

oxidative stress ( J:344896 )

• cerebellar neurons exhibit increased reactive oxygen species (ROS) from 3 to 24 months of age

• active endogenous oxidative stress is detected in cerebellar DNA and protein by 8-OHdG and nitrotyrosine staining, respectively, at 14 months of age

• treatment with antioxidant N-acetylcysteine (NAC) reduces ROS levels in P7 cerebellar mitochondria to levels seen in untreated wild-type controls

homeostasis/metabolism

increased circulating glucose level ( J:344896 )

• mice exhibit significantly higher serum glucose levels at 2 and 10 months of age

• treatment with antioxidant NAC for 1 year restores serum glucose levels

increased circulating lactate level ( J:344896 )

• mice exhibit significantly higher serum lactate levels at 2 and 10 months of age

• treatment with antioxidant NAC for 1 year restores serum lactate levels

increased circulating creatine kinase level ( J:344896 )

• mice exhibit higher serum creatine phosphate kinase (CPK) levels at 2 and 10 months of age

• treatment with antioxidant NAC for 1 year reduces serum CPK levels

increased circulating lactate dehydrogenase level ( J:344896 )

• mice exhibit significantly higher serum lactate dehydrogenase (LDH) levels at 2 and 10 months of age

• treatment with antioxidant NAC for 1 year reduces serum LDH levels

decreased carbon dioxide production ( J:344896 )

• mice show significantly lower CO2 production (VCO2) than age-matched wild-type controls at >12 months of age

increased carbon dioxide production ( J:344896 )

• NAC treatment reduces but does not restore CO2 production to wild-type levels

• mice show significantly higher CO2 production (VCO2) than age-matched wild-type controls at 2 and 10 months of age

decreased oxygen consumption ( J:344896 )

• mice with apparent neurologic defects show significantly lower O2 consumption (VO2) than age-matched wild-type controls at >12 months of age

increased oxygen consumption ( J:344896 )

• mice without apparent neurologic defects show significantly higher O2 consumption (VO2) than age-matched wild-type controls at 2 and 10 months of age

• NAC treatment reduces but does not restore O2 consumption to wild-type levels

decreased respiratory quotient ( J:344896 )

• mice show a significantly lower RER (VCO2/VO2) than age-matched wild-type controls at >12 months of age

increased respiratory quotient ( J:344896 )

• mice show a significantly higher RER (VCO2/VO2) than age-matched wild-type controls at 2 months of age

abnormal carbohydrate metabolism ( J:344896 )

• mice exhibit elevated anaerobic glycolysis to compensate for disturbed energy metabolism

muscle

abnormal muscle fiber mitochondrial morphology ( J:344896 )

• mice exhibit an increased density of mitochondria in muscle with relatively normal mitochondrial structure at 2 and 10 months of age