Mouse Genome Informatics
hm1
    Sod2tm1Cje/Sod2tm1Cje
B6.Cg-Sod2tm1Cje/Mmmh
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mean life span is 0.9 +/- 0.3 days
• at E19 when delivered by cesarean section only 11.6% are homozygous and after natural birth only 8.4% are homozygous
• Background Sensitivity: mean life span is reduced compared to mice on a congenic DBA2/J or hybrid C57BL/6J and DBA2/J background

cardiovascular system
• at E15, moderate to massive enlargement is seen
• dilated left and right ventricles are seen in severe cases
• dilated left and right ventricles are seen in severe cases
• seen with dilated ventricles in severe cases
• at E15, moderate to massive enlargement with the largest hearts having dilated left and right ventricular cavities with thinner muscular walls
• Background Sensitivity: dilated cardiomyopathy is seen on a congenic C57BL/6J background but not in mice on congenic DBA/2J or hybrid C57BL/6J and DBA/2J backgrounds

growth/size
• at E15, surviving mice are 21% smaller than age-matched wild-type littermates

cellular
• increased cardiomyocyte apoptosis after treatment with t-BuOOH to induce oxidative stress

muscle
• at E15, moderate to massive enlargement with the largest hearts having dilated left and right ventricular cavities with thinner muscular walls
• Background Sensitivity: dilated cardiomyopathy is seen on a congenic C57BL/6J background but not in mice on congenic DBA/2J or hybrid C57BL/6J and DBA/2J backgrounds


Mouse Genome Informatics
hm2
    Sod2tm1Cje/Sod2tm1Cje
D2.Cg-Sod2tm1Cje
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mean life span is 8.7 +/- 0.3 days
• Background Sensitivity: mean life span is longer than on a congenic C57BL/6J background but shorter than on a hybrid C57BL/6J DBA/2J background

cardiovascular system
• heart weight to body weight ratios are progressively increased with age and show mild hypertrophy but no myocardial inflammation or fibrosis
• Background Sensitivity: no dilated cardiomyopathy is seen unlike mice on a congenic C57BL/6J or CD-1 background

homeostasis/metabolism
• increase in pO2 and decrease in pCO2 suggest a compensatory increase in respiration as a result of metabolic acidosis
• Background Sensitivity: changes in pO2 and pCO2 are smaller than in mice on a hybrid C57BL/6J DBA/2J background
• Background Sensitivity: seen earlier in congenic mice than in mice on a hybrid C57BL/6J and DBA/2J background
• Background Sensitivity: seen earlier in congenic mice than in mice on a hybrid C57BL/6J and DBA/2J background
• Background Sensitivity: higher levels and seen earlier than in homozygotes on a hybrid C57BL/6J and DBA/2J background
• Background Sensitivity: at P5, heart levels of SOD1 activity are increased unlike mice on a hybrid C57BL/6J DBA/2J background where SOD1 activity is also increased in the brain, liver, and lung
• a 24% decrease in pCO2 is seen
• Background Sensitivity: decrease is smaller than in mice on a hybrid C57BL/6J and DBA/2J background
• a 20% increase in pO2 is seen
• Background Sensitivity: increase is smaller than in mice on a hybrid C57BL/6J and DBA/2J background
• severe metabolic acidosis
• by P5 a rapid decline in HCO3 levels and blood pH is seen
• at P5 urinary organic acid levels are elevated

liver/biliary system
• Background Sensitivity: large amounts of fat in the liver compared to wild-type or homozygotes on a hybrid C57BL/6J and DBA/2J background

cellular
• mithochondrial but not cytoplasmice aconitase activity is reduced in the brain, heart, lung, liver, kidney, and skeletal muscle

renal/urinary system
• at P5 urinary organic acid levels are elevated

growth/size


Mouse Genome Informatics
hm3
    Sod2tm1Cje/Sod2tm1Cje
involves: C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• die between 3 and 13 days of age
• treatment with Manganese 5, 10 ,15, 20-tetrakis (4-benzoic acid) porpryrin (MnTBAP, a superoxide dismutase mimetic that does not cross the blood-brain barrier) increases survival time to a mean life span of 16.4 days compared to 8.3 days without treatment

cardiovascular system
• not detected in mice treated with MnTBAP

nervous system
• 9 of 16 mice older than 12 days of age display focal spongiform changes
• vacuoles are most commonly seen in the reticulotegmental nucleus of the pons, the superior and medioventral periolivary nuclei, and in regions of the motor nucleus of cranial nerves V and VII
• mice older than 12 days of age display symmetric spongiform changes in large areas of the cerebral cortex, primarily in the mid to lower layers of the grey matter and the immediate subcortical white matter
• vacuoles are mostly present in the neuropil and occasionally in the neuronal perikaryon
• 9 of 16 mice older than 12 days of age display focal spongiform changes
• no changes in brain morphology are seen in untreated mice before 10 days of age
• many of the vacuoles are surrounded by thin myelin lamellae
• cross-sectional area is smaller; however, the ultrastructure appears normal in 20 to 21 day old MnTBAP treated mice
• in MnTBAP treated mice

behavior/neurological
• in MnTBAP treated mice
• in MnTBAP treated mice intermittent head tremors develop after P12
• mice treated with MnTBAP develop progressive ataxia starting in the hindlimbs at about P12 and eventually spreading to the frontlimbs
• older mice display a wide-based gait, sway from side to side, and frequently fall with falls sometimes resulting in multiple rolls
• at about P12 MnTBAP treated mice develop ataxia in the hindlimbs with alternating extensor dystonic-like posturing of the hindlimbs and pivoting on the extended limb

vision/eye
• cross-sectional area is smaller; however, the ultrastructure appears normal in 20 to 21 day old MnTBAP treated mice
• in 20 to 21 day old MnTBAP treated mice total retinal thickness, peripheral retinal thickness, and thickness of the combined nerve fiber, ganglion cell, and inner plexiform layers are reduced
• unlike wild-type mice total retinal thickness does not increase between 9-10 and 20-21 days of age
• abnormal mitochondria are more common at 16 and 20-21 days of age in MnTBAP treated mice compared to controls
• mitochondrial abnormalities include foci of swelling, matrix pallor, and disorganization of the cristae
• thinner at 20-21 days of age in MnTBAP treated mice
• the central and overall photoreceptor layer are thinner at 9-10 and 20-21 days of age, respectively, in MnTBAP treated mice

liver/biliary system
• ipid accumulation is decreased with MnTBAP treatment

growth/size
• weight gain is improved with MnTBAP treatment

muscle
• not detected in mice treated with MnTBAP

pigmentation
• abnormal mitochondria are more common at 16 and 20-21 days of age in MnTBAP treated mice compared to controls
• mitochondrial abnormalities include foci of swelling, matrix pallor, and disorganization of the cristae


Mouse Genome Informatics
hm4
    Sod2tm1Cje/Sod2tm1Cje
involves: C57BL/6J * CD-1
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• by 4 - 5 days after birth, 37.5% are dead and almost all die by 10 days of age

cellular
• an increase in oxidative DNA lesions is seen in cells from the heart and brain, but not in liver cells
• at 4 to 6 days of age, succinate dehydrogenase (complex II + III) activity is reduced to 35% and 24% of control in mitochondria from skeletal muscle and heart, respectively
• at 4 to 6 days of age, complex I and citrate synthase activity are reduced to 59% and 32% of control in heart
• liver mitochondria show a 36% decrease in 3-hydroxy-3-methylglutaryl-CoA lyase activity
• aconitase activity is reduced by about 43%, 37%, and 22% in the heart, liver, and brain, respectively; however at P4 - 5 mitochondrial morphology appears normal (J:29899)
• at 9 to 10 days of age aconitase activity is reduced by 89% and 67-76% in the heart and various regions of the brain, respectively (J:52592)

cardiovascular system
• ventricular
• endocardial fibrosis
• enlarged hearts with a dilated left ventricular, reduced left ventricular wall thickness, hypertrophy and endocardial fibrosis but no signs of heart failure are seen

liver/biliary system
• weight is increased relative to body weight
• slightly decreased glutamate oxaloacetate transaminase levels but normal glutamate pyruvate transaminase and bilirubin levels

behavior/neurological
• fatigue rapidly after any exertion

homeostasis/metabolism
• lower serum lactate concentration
• neonates have surface temperatures that are 2.6 degrees C lower than controls
• calcification of the submucosal regions of the small intestine
• compensated metabolic acidosis
• at 9, 10, 14 and 15 days of age increased concentrations of organic acids are found in the urine

hematopoietic system
• seen in neonates

muscle
• enlarged hearts with a dilated left ventricular, reduced left ventricular wall thickness, hypertrophy and endocardial fibrosis but no signs of heart failure are seen
• seen in neonates

growth/size
• mice that survive to 4 - 5 days of age are severely growth retarded

renal/urinary system
• at 9, 10, 14 and 15 days of age increased concentrations of organic acids are found in the urine

integument


Mouse Genome Informatics
hm5
    Sod2tm1Cje/Sod2tm1Cje
involves: C57BL/6J * DBA/2J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mean life span is 15.7 +/- 0.5 days
• Background Sensitivity: mean life span is longer than on a congenic C57BL/6J or DBA/2J background

cardiovascular system
• heart weight to body weight ratios are progressively increased with age and show mild hypertrophy but no myocardial inflammation or fibrosis
• Background Sensitivity: no dilated cardiomyopathy is seen unlike mice on a congenic C57BL/6J or CD-1 background

homeostasis/metabolism
• Background Sensitivity: a steady mild decline in HCO3 levels is seen resulting in maintenance of blood pH in the normal range through P15, unlike the rapid decline seen in mice on a congenic DBA2/J background
• Background Sensitivity: seen later in hybrid mice than in mice on a congenic DBA/2J background
• Background Sensitivity: seen later in hybrid mice than in mice on a congenic DBA/2J background
• Background Sensitivity: lower than in homozygotes on a congenic DBA/2J background
• Background Sensitivity: at P5, brain, heart, lung, and liver levels of SOD1 activity are increased unlike mice on a congenic DBA/2J background where SOD1 activity is increased only in the heart
• a 40% decrease in pCO2 is seen
• Background Sensitivity: decrease is larger than in mice on a congenic DBA/2J background
• a 55% increase in pO2 is seen
• Background Sensitivity: increase is larger than in mice on a congenic DBA/2J background
• Background Sensitivity: milder than in mice on a congenic DBA/2J background
• at P10 and P15 urinary organic acid levels are elevated but no evidence of lactic acidosis is seen at P15

liver/biliary system
N
• Background Sensitivity: do not accumulate large amounts of lipid in the liver unlike mice on a congenic DBA/2J background (J:73998)

cellular
• mitochondrial but not cytoplasmic aconitase activity is reduced in the brain, heart, lung, liver, kidney, and skeletal muscle (J:73998)
• mitochondrial aconitase activities are reduced by 72%, 61%,60%, and 62% in the cortex, thalamus, hippocampus, and brainstem, respectively (J:98007)

behavior/neurological
• visible tremors at P11
• progressive ataxia with age (J:73998)
• at P11 unsteady movement are seen progressing rapidly to truncal instability (J:98007)
• tendency to push or walk backward
• frequent seizures are seen in older mice (J:73998)
• by P14, frequent spontaneous seizures are seen (J:98007)

renal/urinary system
• at P10 and P15 urinary organic acid levels are elevated but no evidence of lactic acidosis is seen at P15

nervous system
• frequent seizures are seen in older mice (J:73998)
• by P14, frequent spontaneous seizures are seen (J:98007)
• vacuolar degeneration is seen in discrete regions
• degenerative changes are detected by P11-13
• degenerative changes are detected by P11-13
• vacuolar degeneration is seen in discrete regions
• vacuolar degeneration is seen in discrete regions
• vacuolar degeneration is seen in deep layers of the motor cortex by P11-13
• in regions of vacuolar degeneration, enlarged and degenerating mitochondria are found in the neurons and axons and the thickness of the myelin sheaths are reduced
• degeneration is first seen around P11-13 and becomes more extensive by P15
• in regions of vacuolar degeneration, enlarged and degenerating mitochondria are found in the neurons and axons and the thickness of the myelin sheaths are reduced

muscle
• proliferation of mitochondria located in clusters near the sarcolemmal membrane

growth/size


Mouse Genome Informatics
ht6
    Sod2tm1Cje/Sod2+
B6.Cg-Sod2tm1Cje/Mmmh
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• no difference in life span or biochemical and physiological indices of aging are detected (J:87514)

tumorigenesis
• more than 80% have neoplastic lesions by 26-28 months of age compared to 41% of wild-type mice; however the types and severity of lesions are similar to those in wild-type mice
• the incidence of mice with multiple tumor types is increased to 66.6% compared to 18.5% in wild-type mice
• incidence is increased to 61% compared to 22% in wild-type mice

cellular
• aconitase and NADH-oxidoreductase (with CoQ as a substrate) activities are reduced by 35% and 45%, respectively, in hearts; however, mitochondrial fumerase and cytosolic aconitase and glutamine synthetase activities are not reduced
• the speed of induction of permeability transition by calcium is significantly increased in heart mitochondria
• the respiratory control ratio for complex I and state 3 respiration (with glutamate and malate as substrates) are reduced by 37%; however, state 4 respiration is similar to controls
• significantly higher levels of oxidative DNA damage (measured as 8oxodG) are detected in mitochondrial and nuclear DNA at all ages examined (J:87514)
• treatment with 50 mg paraquat / kg resulted in loss of 30% of heterozygotes within 4 days, unlike wild-type mice which all survived (J:87514)
• increased cardiomyocyte apoptosis after treatment with t-BuOOH to induce oxidative stress compared to controls but less than in homozygous cells (J:108637)


Mouse Genome Informatics
ht7
    Sod2tm1Cje/Sod2+
D2.Cg-Sod2tm1Cje
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cellular
• at P5 mithochondrial but not cytoplasmice aconitase activity is reduced in the brain, heart, lung, liver, kidney, and skeletal muscle
• this reduction is not as severe as in homozygotes


Mouse Genome Informatics
ht8
    Sod2tm1Cje/Sod2+
involves: C57BL/6J * CD-1
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cellular
• increased 3-fold at 20 - 25 months of age
• liver mitochondria are more prone to permeability transition following calcium addition
• liver mitochondrial membrane electrochemical potential is lower than in wild-type
• liver mitochondrial oxidative phosphorylation complexes I, II, II + III, and IV and citrate synthase are elevated 25% - 75% in 20 to 25 month old mice
• state III respiratory rate is reduced in liver cells at 5 and 10 - 14 months of age, but by 20 - 25 months control rates decrease so that they are similar to homozygotes
• state IV respiration rate is increased in 10 - 14 and 20 - 25 month old mice but not in young (5 month old) mice
• state III respiratory control ratios are reduced in young and middle aged mice but closer to normal in old mice
• at 10 - 14 months of age, liver mitochondria contain twice as much lipid hydroperoxides as in controls, but lipid peroxide levels decrease in old homozygotes

liver/biliary system
• increased 3-fold at 20 - 25 months of age


Mouse Genome Informatics
ht9
    Sod2tm1Cje/Sod2+
involves: C57BL/6J * DBA/2J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cellular
• at P5 mitochondrial but not cytoplasmic aconitase activity is reduced in the brain, heart, lung, liver, kidney, and skeletal muscle
• this reduction is not as severe as in homozygotes


Mouse Genome Informatics
cx10
    Sod2tm1Cje/Sod2+
Tg(SOD1*G93A)1Gur/0

involves: C57BL/6 * CD-1 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• accelerated disease progression
• shorter lifespans than Tg(SOD1*G93A)1Gur mice
• mean decrease in survival is 11 days

behavior/neurological
• worse motor performance in rotorod test than Tg(SOD1*G93A)1Gur mice starting from 106 days of age

nervous system
• decreased number of total neurons within the substatia nigra at 110 days of age
• microvesiculation within large ventral horn motor neurons at 90 days of age
• accelerated disease progression
• decreased number of total neurons within the ventral horns of the lumbar cord at 90 days of age
• greater neuronal loss than that in Tg(SOD1*G93A)1Gur mice at 110 days of age
• decreased number of total neurons within the ventral horns of the lumbar cord starting at 90 days of age
• greater neuronal loss than that in Tg(SOD1*G93A)1Gur mice at 110 days of age
• atrophy of the lumbar spinal cord starting at 90 days of age


Mouse Genome Informatics
cx11
    Sod2tm1Cje/Sod2tm1Cje
SvtmsC57BL/6J/SvtmsC57BL/6J

involves: C57BL/6J * DBA/2J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• increased postnatal lethality
• shorter survival time (less than 6 days)


Mouse Genome Informatics
cx12
    Sod2tm1Cje/Sod2tm1Cje
SvtmsC57BL/6J/SvtmsDBA/2J

involves: C57BL/6J * DBA/2J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• decreased postnatal lethality (J:108213)
• increased survival time (>6 days) (J:108213)