Mouse Genome Informatics
hm1
    Nos1tm1Plh/Nos1tm1Plh
B6.129S4-Nos1tm1Plh
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
N
• unlike mice null for Nos3, ischemia induced retinal neovascularization is not significantly different from controls (J:106207)
• knockouts show a 58% decrease in neovascularization at sites of laser-induced Bruch's membrane rupture compared to heterozygous littermates
• kainic acid injection of hippocampi does not cause blood-brain barrier breakdown

behavior/neurological
N
• Background Sensitivity: unlike mice on a mixed 129S4/SvJae and C57BL/6J background, congenic male mice do not display significantly increased aggression compared to wild-type controls (J:67776)
• lactating females display decreased aggression towards intruder males
• about a 90% decrease in the amount of time lactating females spend actively attacking or biting an intruder male
• increase in the number and duration of attacks and decrease in the latency to attack in a resident intruder assay
• treatment with a serotonin precursor dramatically reduces aggressive behavior
• significantly higher concentrations of serotonin receptor agonists are required to reduce aggressive behavior than in wild-type controls
• lactating females display decreased aggression towards intruder males (J:57543)
• about a 90% decrease in the amount of time lactating females spend actively attacking or biting an intruder male (J:57543)
• in contrast to the decrease in maternal aggression, no defect in pup retrieval is detected (J:57543)
• when exposed to hyperbaric oxygen (greater than 99% oxygen) at 5 ATA for 60 min the time to first seizure in freely moving mice is significantly longer compared to similarly treated wild-type mice

other phenotype
• pups of homozygous females weigh more than pups of wild-type females

homeostasis/metabolism
• kainic acid does not cause the hippocampal neurons to degenerate
• elevated plasma triglycerides
• total serotonin content is increased in the cerebral cortex, hypothalamus, hippocampus, midbrain and cerebellum
• as no change is seen on the concentration of the serotonin metabolite, 5-HIAA, the 5-HIAA to serotonin (5-HT) ratio is reduced in the cortex, hypothalamus, midbrain, and cerebellum indicating a decrease in serotonin turnover
• functional deficits following middle cerebral artery obstruction are reduced compared to wild-type controls
• infarction sized induced by middle cerebral artery obstruction is reduced in males, but not in females, compared to wild-type controls
• however, infarct size is increased compared to mice hemizygous for Tg(SOD1)76Dpr

vision/eye
• knockouts show a 58% decrease in neovascularization at sites of laser-induced Bruch's membrane rupture compared to heterozygous littermates

nervous system
• in anesthetized mice the latency to hyperbaric oxygen (greater than 99% oxygen) at 5 ATA induced EEG seizure is increased compared to similarly treated wild-type mice
• striatal accumulation of 3-nitrotyrosine during hyperbaric oxygen exposure is decreased compared to similarly treated wild-type mice
• when exposed to hyperbaric oxygen (greater than 99% oxygen) at 5 ATA for 60 min the time to first seizure in freely moving mice is significantly longer compared to similarly treated wild-type mice
• kainic acid injection of hippocampi does not cause blood-brain barrier breakdown
• kainic acid does not cause the hippocampal neurons to degenerate
• functional deficits following middle cerebral artery obstruction are reduced compared to wild-type controls
• infarction sized induced by middle cerebral artery obstruction is reduced in males, but not in females, compared to wild-type controls
• however, infarct size is increased compared to mice hemizygous for Tg(SOD1)76Dpr

cellular
• kainic acid does not cause the hippocampal neurons to degenerate


Mouse Genome Informatics
hm2
    Nos1tm1Plh/Nos1tm1Plh
B6.129S4-Nos1tm1Plh/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size
• in males only

muscle
• decrease in skeletal muscle weight in males
• peak twitch force is decreased in the tibialis anterior muscle of male mice
• decrease in the maximal tetanic force generating capacity of the tibialis anterior muscle in males
• however, when normalized to muscle size the force generating capacity is not significantly different from wild-type controls
• tibialis anterior muscle displays an increase in the susceptibility to contraction induced fatigue in both males and females

immune system
• fever in response to LPS injection is partially reduced compared to wild-type controls
• reduction in fever response mainly occurs during the early phase of fever response
• however, fever in response to turpentine injection is not different from controls


Mouse Genome Informatics
hm3
    Nos1tm1Plh/Nos1tm1Plh
B6;129S4-Nos1tm1Plh/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
N
• increased aggressive behavior is not seen in males unlike in other reports (J:83571)
• mice spend less time in REM sleep as a result of fewer REM episodes and lengthened duration of the inter REM intervals
• however, there is no significant difference in the amount of time spent in non-REM sleep and mice display normal diurnal variation in sleep patterns

nervous system
• during non-REM sleep the absolute value of slow wave activity is increased

skeleton
• bone mineral content is increased
• bone mineral density is increased
• trabecular bone tends to extend deeper into the metaphysis
• indices of bone formation and resorption are lower
• in culture RANKL and M-CSF induced osteoclast formation are increased

hematopoietic system
• in culture RANKL and M-CSF induced osteoclast formation are increased

immune system
• in culture RANKL and M-CSF induced osteoclast formation are increased

cellular
• in culture RANKL and M-CSF induced osteoclast formation are increased


Mouse Genome Informatics
hm4
    Nos1tm1Plh/Nos1tm1Plh
involves: 129S4/SvJae
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• about 80% survival rate at 10 months of age
• about 20% die before 10 months of age

homeostasis/metabolism
• following carotid artery ligation the extent of neointimal formation is increased and luminal narrowing is worsened compared to wild-type controls
• myocardial infarct size following 30 min of global ischemia is increased compared to controls
• the size of striatal lesions induced by malonate are significantly reduced compared to similarly treated controls
• insulin resistance in peripheral tissues
• 24 h after aspiration bulbectomy the number of apoptotic cells in the piriform cortex is reduced compared to similarly treated wild-type mice
• following occlusion of the middle cerebral artery infarct size is decreased

nervous system
N
• despite the ability of NOS inhibitors to decrease long term potentiation, no significant decrease in long term potentiation is detected at 1 h after tetanus (J:37956)
• unlike cerebral blood flow, the intensity of neural activation induced by perioral stimulation is not significantly different from controls (J:84255)
• 24 h after aspiration bulbectomy the number of apoptotic cells in the piriform cortex is reduced compared to similarly treated wild-type mice
• the size of striatal lesions induced by malonate are significantly reduced compared to similarly treated controls
• following occlusion of the middle cerebral artery infarct size is decreased
• following a theta burst protocol at a weak intensity enhancement of EPSPs during the first 3 minutes after stimulation is significantly small compared to controls
• however, no significant differences are detected when a stronger intensity stimulation is used
• stimulation of parallel fibers with a 50 msec postsynaptic depolarizations fails to induce long term depression in Purkinje cells
• addition of uncaged NO or photoreleased cGMP to the stimulation protocol also fails to induce long term depression in Purkinje cells, unlike in wild-type mice
• glutamate release after NMDA stimulation is significantly attenuated in the cerebral cortex, partially reduced in the striatum but unaffected in the hippocampus

behavior/neurological
N
• unlike in earlier reports males show no signs of increased aggression (J:42548)
• no defects in circadian rhythms are detected in a wheel running assay either under entrained or free running conditions (J:56005)
• mice show no improvement in their latency to fall off a pole or plank in the dark versus the light phase, unlike in wild-type controls resulting in deficits in balance compared to wild-type mice during the dark phase

digestive/alimentary system
• lower esophageal sphincters fail to display electrical field stimulation (60 V, 5 Hz) induced relaxation or rebound contraction (J:56948)
• the mean resting lower esophageal sphincter pressure is significantly higher (J:70182)
• swallowing induced lower esophageal sphincter relaxation is significantly attenuated (J:70182)
• mice show a range of responses to pharyngeal stimulation including no relaxation, partial relaxation , and sporadic near complete relaxation of the lower esophageal sphincter (J:70182)
• efferent vagal stimulation induced lower esophageal sphincter relaxation is significantly attenuated (J:70182)

immune system
• increase in baseline rolling
• treatment with an anti-P-selectin antibody significantly reduces the rolling response in mutant but not in wild-type mice
• treatment with a low dose of thrombin significantly increases rolling in mutant but not in wild-type mice
• dramatic increase in baseline leukocyte adherence
• treatment with an anti-P-selectin antibody significantly reduces the adhesion response in mutant but not in wild-type mice
• following thioglycollate injection neutrophil accumulation in the peritoneum is significantly enhanced compared to wild-type mice

muscle
• the resting membrane potential of jejunal smooth muscle cells is depolarized about 5 mV compared to wild type cells
• hyperpolarization and induction of an inhibitory junction potential in response to electrical field stimulation under nonadrenergic noncholinergic conditions in jejunal muscle strips are markedly reduced
• lower esophageal sphincters fail to display electrical field stimulation (60 V, 5 Hz) induced relaxation or rebound contraction (J:56948)
• the mean resting lower esophageal sphincter pressure is significantly higher (J:70182)
• swallowing induced lower esophageal sphincter relaxation is significantly attenuated (J:70182)
• mice show a range of responses to pharyngeal stimulation including no relaxation, partial relaxation , and sporadic near complete relaxation of the lower esophageal sphincter (J:70182)
• efferent vagal stimulation induced lower esophageal sphincter relaxation is significantly attenuated (J:70182)
• lower esophageal sphincters fail to display electrical field stimulation (60 V, 5 Hz) induced relaxation or rebound contraction (J:56948)
• the decrease in muscle contractions in jejunal muscle strips in response to electrical field stimulation is markedly reduced (J:89581)

cardiovascular system
N
• unlike in mice null for Nos3 no significant abnormalities in hypoxic pulmonary vasoconstriction, vasodilation in response to bradykinin, or right ventricle systolic pressure are detected (J:57624)
• the increase in cerebral blood flow induced by glutamate, perioral stimulation, or harmaline is significantly attenuated
• in isolated perfused hearts
• however, coronary flow per beat is not significantly different from controls
• following carotid artery ligation the extent of neointimal formation is increased and luminal narrowing is worsened compared to wild-type controls
• myocardial infarct size following 30 min of global ischemia is increased compared to controls

vision/eye
N
• no defects are detected in visual acuity (J:56005)

reproductive system
N
• unlike in Nos3 null mice, the increase in maximal penile intracavernous pressure induced by papaverine is not significantly different from wild-type controls (J:89704)

growth/size

cellular
• the size of striatal lesions induced by malonate are significantly reduced compared to similarly treated controls
• increase in baseline rolling
• treatment with an anti-P-selectin antibody significantly reduces the rolling response in mutant but not in wild-type mice
• treatment with a low dose of thrombin significantly increases rolling in mutant but not in wild-type mice
• dramatic increase in baseline leukocyte adherence
• treatment with an anti-P-selectin antibody significantly reduces the adhesion response in mutant but not in wild-type mice

hematopoietic system
• increase in baseline rolling
• treatment with an anti-P-selectin antibody significantly reduces the rolling response in mutant but not in wild-type mice
• treatment with a low dose of thrombin significantly increases rolling in mutant but not in wild-type mice
• dramatic increase in baseline leukocyte adherence
• treatment with an anti-P-selectin antibody significantly reduces the adhesion response in mutant but not in wild-type mice
• following thioglycollate injection neutrophil accumulation in the peritoneum is significantly enhanced compared to wild-type mice

Mouse Models of Human Disease
OMIM IDRef(s)
Achalasia, Familial Esophageal 200400 J:70182


Mouse Genome Informatics
hm5
    Nos1tm1Plh/Nos1tm1Plh
involves: 129S4/SvJae * C57BL/10ScSn
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
muscle
N
• no abnormalities in muscle morphology are detected (J:48851)


Mouse Genome Informatics
hm6
    Nos1tm1Plh/Nos1tm1Plh
involves: 129S4/SvJae * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• in anesthetized mice under 12% oxygen all mutant mice survived while 4 of 14 wild-type mice died
• survival at 20 months is reduced compared to Nos3 null mice
• slight increase in premature death (J:16390)
• survival at 20 months is reduced compared to Nos3 null mice (J:129064)
• the relative risk of death by 20 months of age is 2.5 times higher than in Nos3 null mice (J:129064)

digestive/alimentary system
• hypertrophy of the pyloric sphincter and the circular muscle layer
• with age, the stomachs lose their interior folds and undergo thinning of the walls, however the intestine appears normal
• stomach dilation, however architecture of the stomach layers is preserved

reproductive system
• ovulatory efficiency (number oocytes recovered divided by the number of ovarian rupture sites) is reduced in homozygotes (J:89701)
• significantly fewer oocytes are recovered following gonadotropin-stimulated ovulation in homozygous mutant females compared to wild-type females (J:89701)

nervous system
N
• homozygous mice do not exhibit defects in brain structure or neuron degeneration (J:16390)
• electron microscopy analysis indicates a lower density of mitochondria in the cortex of the brain
• however, the ratio of mitochondrial to nuclear DNA is similar to controls
• motor neurons display a significant decrease in the number of dendritic branches
• however, the number of primary dendrites, the longest dendritic path from a cell, and cell body size are not different from wild-type controls
• motor neurons display a significant decrease in the number of dendritic branches
• decrease in the number of branches is first detected at about 100 um from the cell body with a peak in the decrease between about 160 - 260 um
• difference in branch number is limited to third and fourth order branches
• however, the number of primary dendrites and the longest dendritic path from a cell are not different from wild-type controls
• delay in Wallerian degeneration following transection of the sciatic nerve in the right hindlimb
• following transection of the sciatic nerve in the right hindlimb time to recovery of motor function is delayed
• following transection of the sciatic nerve in the right hindlimb uncontrolled sprouting is increased
• however, myelination following transection is not significantly different from controls

muscle
• muscle atrophy induced by transection of the sciatic nerve in the right hindlimb is reduced
• attenuation of the beta-adrenergic inotropic responses indicating a decrease in myocardial contractile reserve
• isolated ventricular myocytes display greater overall shortening at all stimulation frequencies between 0.2 and 10 Hz
• shortening in response to beta-adrenergic stimulation is greatly enhanced
• time to 50% relaxation is increased

behavior/neurological
• when placed with females in estrus males display excessive and inappropriate mounting
• in a resident intruder assay males display more aggressive encounters and initiate more of the aggressive encounters compared to wild-type mice
• for males latency to first attack is reduced to about 1/5 that of wild-type mice
• male mice display submissive postures about 1/10 as frequently as wild-type controls
• for males the duration of aggressive encounters is increased
• no increase in aggression is seen in females
• when placed with females in estrus males display excessive and inappropriate mounting
• the number of mounts fails to decrease significantly 1 h after the introduction of an anestrus female to the cage
• by 7 to 8 h after introduction of a female, the number of mounts made by males is 2 to 3 times greater compared to wild-type males

homeostasis/metabolism
N
• despite the increase in aggressive and sexual behaviors, no significant difference is detected in blood testosterone levels compared to wild-type males (J:29970)
• in awake mice carbon dioxide production is significantly decreased during 12% oxygen compared to 100% oxygen in mutant but not in wild-type mice
• in awake mice the magnitude of the decrease in oxygen consumption under 21% or 12% oxygen is greater than that in wild-type controls
• sodium cyanide induced respiratory stimulation is increased in mutants compared to wild-type mice

respiratory system
• in awake mice the magnitude of the increases in tidal volume at 21% and 12% oxygen are greater than in wild-type controls
• anesthetized mice under 21% or 12% oxygen show period increases in respiratory rate not seen in wild-type mice
• in awake mice, the magnitude of the decrease in respiratory rate following brief exposure to 100% oxygen was greater than that in wild-type mice
• in awake and anesthetized mice the magnitude of the increases in respiratory rate at 21% and 12% oxygen are greater than in wild-type controls
• anesthetized mice do not display respiratory depression under 12% oxygen, unlike wild-type controls
• in anesthetized mutant mice the increase in ventilation under 21% oxygen results from an increase in both respiratory rate and tidal phrenic activity, unlike in wild-type mice where only tidal phrenic activity is increased
• sodium cyanide induced respiratory stimulation is increased in mutants compared to wild-type mice
• in awake mice the significant increases are seen in minute ventilation at both 21% and 12% oxygen unlike in wild-type controls where increases are seen only at 12% oxygen
• in awake and anesthetized mice the magnitude of the increase in minute ventilation is greater at both 21% and 12% oxygen compared to wild-type controls

cardiovascular system
• attenuation of the beta-adrenergic inotropic responses indicating a decrease in myocardial contractile reserve
• isolated ventricular myocytes display greater overall shortening at all stimulation frequencies between 0.2 and 10 Hz
• shortening in response to beta-adrenergic stimulation is greatly enhanced
• time to 50% relaxation is increased

cellular
• despite similar ratios of mitochondrial to nuclear DNA the amount of citrate synthase is significantly increased in homogenates from the heart, kidney and liver

liver/biliary system
• lipid content of the liver is increased (J:104558)
• unlike in wild-type livers, glycogen content is increased in zone 3 relative to zone 1 of the liver (J:133437)
• fat droplets are absent from the cytosol of hepatocytes

renal/urinary system
• electron microscopy analysis indicates a lower density of mitochondria in tubule cells of the kidney
• however, the ratio of mitochondrial to nuclear DNA is similar to controls

growth/size
N
• no difference in body weight is detected at 1 year of age (J:133437)

Mouse Models of Human Disease
OMIM IDRef(s)
Pyloric Stenosis, Infantile Hypertrophic, 1; IHPS1 179010 J:16390


Mouse Genome Informatics
hm7
    Nos1tm1Plh/Nos1tm1Plh
involves: 129S4/SvJae * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
renal/urinary system
• increase in urine bicarbonate concentration
• increase in urine pH
• the rate of bicarbonate absorption is reduced in the proximal tubules
• the rate of net fluid absorption is reduced in the proximal tubules

cardiovascular system
• atria display higher baseline heart rates
• decrease in heart rate in response to vagal nerve stimulation is slower

homeostasis/metabolism
N
• despite differences in behavioral responses to alcohol, no differences in blood alcohol elimination are detected (J:79215)
• the rate of net fluid absorption is reduced in the proximal tubules
• arterial blood pH and bicarbonate concentrations are reduced resulting in a modest but significant metabolic acidosis
• increase in urine bicarbonate concentration
• increase in urine pH

behavior/neurological
• mice consume more alcohol when presented with solutions containing high concentrations of alcohol (greater than 8% alcohol) compared to wild-type controls
• however, when presented with dilute solutions of alcohol (2 - 4%), alcohol consumption does not differ from controls
• following dosing with 2.5 or 4.5 gm/kg mice regain their righting reflex faster compared to similarly treated wild-type controls
• mice fail to develop tolerance to alcohol induced hypothermia following multiple ethanol injection
• the concentration dependent increase in sucrose preference is more pronounced in mutants compared to wild-type controls
• however, the concentration dependent aversion to quinine is not significantly different from controls
• Background Sensitivity: unlike mice on a congenic C57BL/6J background, male mice display increased aggression
• Background Sensitivity: mice display increased aggression compared to C57BL/6J mice but not compared to 129S2/SvPas mice
• in a forced swim test mice spend more time actively swimming and less time immobile compared to wild-type controls
• increase in grooming behavior is seen in mice in an open field and during an elevated plus maze assay suggesting an increase in the amount of stress mice experience under these conditions
• seen in mice in an open field and during an elevated plus maze assay suggesting an increase in the amount of stress mice experience under these conditions
• impaired performance during memory recall trials in a Morris water maze
• however, performance in the less stressful multiple T maze is improved compared to controls
• in the last trial mice spend more time on the rotarod compared to wild-type controls

digestive/alimentary system
N
• unlike in human patients with Infantile Hypertrophic Pyloric Stenosis, the luminal aperture of the pyloric sphincter is not significantly smaller in relaxed tissues compared to wild type controls (J:64225)
• diffuse enlargement
• diffuse enlargement
• pyloric sphincter thickness is increased by 17% compared to controls
• diffuse enlargement
• weight and volume are increased
• muscular thickening is seen throughout the stomach
• stomachs often contain bezoars even after 2 days of fasting
• gastric emptying of solids and liquids is delayed

muscle
• pyloric sphincter thickness is increased by 17% compared to controls

Mouse Models of Human Disease
OMIM IDRef(s)
NOT Pyloric Stenosis, Infantile Hypertrophic, 1; IHPS1 179010 J:64225


Mouse Genome Informatics
ht8
    Nos1tm1Plh/Nos1+
B6.129S4-Nos1tm1Plh
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• exercise training fails to augment the phenylephrine induced pulse interval response
• exercise training fails to augment the phenylephrine induced or vagal nerve stimulation bradycardia responses
• no differences in heart rate responses are detected in the absence of exercise training

homeostasis/metabolism
• exercise training fails to augment the phenylephrine induced bradycardia and pulse interval responses
• no differences in phenylephrine induced responses are seen in untrained mice


Mouse Genome Informatics
cx9
    Nos1tm1Plh/Nos1tm1Plh
Nos3tm1Plh/Nos3tm1Plh

B6.129S4-Nos3tm1Plh Nos1tm1Plh
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• myocyte hypertrophy is detected by 4-5 months of age
• hypertrophy becomes more severe with age
• areas of focal interstitial fibrosis are seen in old (14-15 months of age) mice
• prior to the development of frank left ventricular hypertrophy indices of myocardial contractility are elevated
• indices of contractility are also increased in old mice
• ejection fraction is increased in old mice
• passive diastolic relaxation appears impaired based on an increase in the time to peak filling
• decrease in left ventricular end diastolic pressure in young mice

muscle
• prior to the development of frank left ventricular hypertrophy indices of myocardial contractility are elevated
• indices of contractility are also increased in old mice
• ejection fraction is increased in old mice
• passive diastolic relaxation appears impaired based on an increase in the time to peak filling


Mouse Genome Informatics
cx10
    Nos1tm1Plh/Nos1tm1Plh
Nos2tm1Lau/Nos2tm1Lau

involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• fewer than expected double homozygotes are born, no time of lethality provided


Mouse Genome Informatics
cx11
    Nos1tm1Plh/Nos1tm1Plh
Nos3tm1Unc/Nos3tm1Unc

involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• fewer than expected double homozygotes are born, no time of lethality provided


Mouse Genome Informatics
cx12
    Hmox2tm1Poss/Hmox2tm1Poss
Nos1tm1Plh/Nos1tm1Plh

involves: 129S2/SvPas * 129S4/SvJae
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
muscle
• the resting membrane potential of jejunal smooth muscle cells is depolarized about 13 mV compared to wild type cells
• hyperpolarization and induction of an inhibitory junction potential in response to electrical field stimulation in jejunal muscle strips are markedly reduced
• unlike in wild-type controls electrical field stimulation under nonadrenergic noncholinergic conditions induces a depolarization of membrane potential in jejunal smooth muscle cells
• the decrease in muscle contractions in jejunal muscle strips in response to electrical field stimulation is markedly reduced


Mouse Genome Informatics
cx13
    Nos1tm1Plh/Nos1tm1Plh
Nos3tm1Plh/Nos3tm1Plh

involves: 129S4/SvJae
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• 60-80% survival rate at 10 months of age
• about 20-40% die before 10 months of age

reproductive system
• slight reduction in the number of offspring produced from breeding pairs

cardiovascular system

homeostasis/metabolism

behavior/neurological

nervous system
N
• unlike long term potentiation, long term depression and paired pulse facilitation are not significantly different from controls and no significant abnormalities in hippocampal morphology are detected (J:37956)
• at P21 the ipsilateral retinocollicular projections are spread across cover more of the medio-lateral axis of and extend further caudally in the superior colliculus rather than being confined to the most medial and rostral regions as in wild-type controls
• at P28, ipsilateral retinocollicular projections remain more broadly distributed in the superior colliculus
• however, by P90 ipsilateral retinocollicular projections resemble those in wild-type controls indicating a delay in refinement rather than a block
• unlike in either single homozygote, hippocampal long term potentiation is significantly reduced at 1 h after tetanus
• however, long term potentiation in the stratum oriens is not significantly different from controls

renal/urinary system


Mouse Genome Informatics
cx14
    Nos1tm1Plh/Nos1tm1Plh
Nos2tm1Mrl/Nos2tm1Mrl
Nos3tm1Plh/Nos3tm1Plh

involves: 129S4/SvJae * 129S7/SvEvBrd
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Renal tubular apoptosis, regeneration, glomerulosclerosis and glomerular thrombus formation in Nos1tm1Plh/Nos1tm1Plh Nos2tm1Mrl/Nos2tm1Mrl Nos3tm1Plh/Nos3tm1Plh mice

mortality/aging
• only 3 of 13 mutants survive to 10 months of age
• only 3 of 13 mutants survive to 10 months of age

reproductive system
• the number of offspring produced from breeding pairs is significantly smaller than in wild-type

cardiovascular system
• all mutants that die show wall thickening, perivascular fibrosis, and adventitial mast cell infiltration of the coronary arteries
• glomerular thrombus formation
• 2 mutants that die within 10 months of age, have pulmonary and liver congestion
• in 2 mutants that die within 10 months of age
• in 2 mutants that die within 10 months of age
• heart rate is significantly lower than in wild-type, but similar to that of single Nos3 homozygotes, double Nos1/Nos3 homozygotes, and double Nos2/Nos3 homozygotes
• hypertension is similar to single Nos3 homozygotes, double Nos1/Nos3 homozygotes, and double Nos2/Nos3 homozygotes
• systolic blood pressure is significantly higher in mutants than wild-type under conscious conditions
• the two mutants with pulmonary and liver congestion and acute renal tubular necrosis exhibit acute circulatory failure

homeostasis/metabolism
• glomerular thrombus formation
• plasma concentrations of creatinine tend to be higher
• plasma osmolality is increased
• plasma concentrations of urea nitrogen are higher
• serum concentration is increased
• mutants exhibit only 2.4% and 3.6% of normal plasma and urinary NO levels, respectively
• renal prostacyclin levels are significantly higher in 1 week old mutants than in wild-type

renal/urinary system
• glomerular thrombus formation
• renal tubular lesions are seen predominantly in distal and collecting tubules than in proximal tubules
• glomerular thrombus formation
• 2 mutants that die within 10 months of age have acute renal tubular necrosis
• renal responsiveness to the anti-diuretic hormone, vasopressin, is reduced compared to wild-type, although central vasopressin release in unchanged
• impaired renal cAMP production
• hypotonic polyuria

behavior/neurological

digestive/alimentary system
• pyloric sphincter hypertrophy
• 3 of 5 mutants show enlargement of the stomach

liver/biliary system
• in 2 mutants that die within 10 months of age

respiratory system
• in 2 mutants that die within 10 months of age

skeleton
• at all time points
• increases slightly at 12 weeks of age
• trabecular bone in the proximal tibia is increased
• increased osteoclast function
• higher in females than in males
• bone formation rate and mineral apposition rate are increased
• higher in females than in males

hematopoietic system
• increased osteoclast function
• higher in females than in males

immune system
• increased osteoclast function
• higher in females than in males

muscle
• pyloric sphincter hypertrophy

cellular

Mouse Models of Human Disease
OMIM IDRef(s)
Diabetes Insipidus, Nephrogenic, Autosomal 125800 J:100308


Mouse Genome Informatics
cx15
    Nos1tm1Plh/Nos1tm1Plh
Nos2tm1Mrl/Nos2tm1Mrl

involves: 129S4/SvJae * 129S7/SvEvBrd
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• 60-80% survival rate at 10 months of age
• about 20-40% die before 10 months of age

reproductive system
• slight reduction in the number of offspring produced from breeding pairs

homeostasis/metabolism
• plasma osmolality is increased

renal/urinary system

behavior/neurological


Mouse Genome Informatics
cx16
    Nos1tm1Plh/Nos1tm1Plh
Nos2tm1Mrl/Nos2tm1Mrl
Nos3tm1Plh/Nos3tm1Plh

involves: 129S4/SvJae * 129S7/SvEvBrd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• 85% of males die within 11 months whereas only 35-40% of males of any double homozygous genotype die at that time point

cardiovascular system
• in most of the vasculature
• lipid accumulation in the aorta
• anterior and posterior ventricular walls are thickened
• endothelium dependent relaxation lacking
• no vascular lesions in 2 month old males
• significant neointimal formation at 5 months
• medial thickening at 5 months
• perivascular fibrosis of large epicardial coronary arteries and renal arteries

adipose tissue
• perirenal and epididymal white adipose weights are increased

homeostasis/metabolism
• no vascular lesions in 2 month old males
• significant neointimal formation at 5 months
• medial thickening at 5 months
• significantly increased after i.v. glucose
• elevated plasma triglycerides


Mouse Genome Informatics
cx17
    Nos1tm1Plh/Nos1tm1Plh
Tg(SOD1)76Dpr/0

involves: 129S4/SvJae * C3H/HeJ * C57BL/6 * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• functional deficits following middle cerebral artery obstruction are reduced compared to wild-type controls but not compared to mice hemizygous for Tg(SOD1)76Dpr alone
• infarction sized induced by middle cerebral artery obstruction is reduced compared to wild-type controls
• however, the reduction in infarction size is not significantly different from that seen in mice hemizygous for Tg(SOD1)76Dpr alone

homeostasis/metabolism
• functional deficits following middle cerebral artery obstruction are reduced compared to wild-type controls but not compared to mice hemizygous for Tg(SOD1)76Dpr alone
• infarction sized induced by middle cerebral artery obstruction is reduced compared to wild-type controls
• however, the reduction in infarction size is not significantly different from that seen in mice hemizygous for Tg(SOD1)76Dpr alone


Mouse Genome Informatics
cx18
    Dmdmdx/Y
Nos1tm1Plh/Nos1tm1Plh

involves: 129S4/SvJae * C57BL/10ScSn
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
muscle
• mice show severe dystrophic changes in the muscle (J:48851)

homeostasis/metabolism
• marked elevation of pyruvate kinase levels is detectable by P21, absence of Nos1 expression does not significantly change pyruvate kinase levels compared to mice hemizygous for Dmdmdx and heterozygous for Nos1tm1Plh (J:48851)


Mouse Genome Informatics
cx19
    Dmdmdx/Dmd+
Nos1tm1Plh/Nos1tm1Plh

involves: 129S4/SvJae * C57BL/10ScSn
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
muscle
• mice show isolated dystrophic changes in the muscle (J:48851)

homeostasis/metabolism
• moderate elevation of pyruvate kinase levels is detectable by P21, absence of Nos1 expression does not significantly change pyruvate kinase levels compared to mice heterozygous for both Dmdmdx and Nos1tm1Plh (J:48851)


Mouse Genome Informatics
cx20
    Nos1tm1Plh/Nos1tm1Plh
Nos3tm1Plh/Nos3tm1Plh

involves: 129S4/SvJae * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• survival at 20 months is reduced compared to Nos3 or Nos1 single mutant mice
• survival at 20 months is reduced compared to Nos3 or Nos1 single mutant mice
• the relative risk of death by 20 months of age is increased 7.3 fold compared to Nos3 single mutants and 3.0 fold compared to Nos1 single mutants
• mortality is increased in males compared to females

cardiovascular system
• develop age related concentric remodeling with marked increase in relative wall thickness
• increase in wall thickness and decrease in systolic and diastolic dimensions with age
• attenuation of the beta-adrenergic inotropic responses indicating a decrease in myocardial contractile reserve
• increase in basal contractility
• hypertrophy is associated with hypercontractility
• hypertrophy is associated with increased diastolic stiffness
• relative to wild-type mice and Nos3 single mutants
• identical to that in Nos3 single mutants

muscle
• attenuation of the beta-adrenergic inotropic responses indicating a decrease in myocardial contractile reserve
• increase in basal contractility
• hypertrophy is associated with hypercontractility
• hypertrophy is associated with increased diastolic stiffness


Mouse Genome Informatics
cx21
    Nos1tm1Plh/Nos1tm1Plh
Tg(RHO-VEGFA)V-6Camp/0

involves: 129S4/SvJae * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• compared to mice carrying Tg(RHO-VEGFA)V-6Camp and heterozygous for Nos1tm1Plh neovascularization of the retina is significantly reduced