Mouse Genome Informatics
hm1
    Nos2tm1Mrl/Nos2tm1Mrl
B6.129S7-Nos2tm1Mrl
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
skeleton
• in vitro differentiation is markedly attenuated
• decreased by 25%
• resorption activity is considerably decreased
• bone mineral density of the femur is elevated at both 4 and 9 weeks of age
• total bone volume is increased
• increased cortical bone mass
• trabecular bone thickness and connectivity unchanged from controls

craniofacial
• distance between cementoenamel junction and alveolar bone crest is greater than for controls from 6 weeks on (without any bacterial challenge)

immune system
• in vitro differentiation is markedly attenuated
• decreased by 25%
• resorption activity is considerably decreased
• do not respond to oral infection with Porphyromas gingivalis by bone loss
• serum levels of specific IgG are comparable to controls

homeostasis/metabolism
• slightly elevated relative to controls

hematopoietic system
• in vitro differentiation is markedly attenuated
• decreased by 25%
• resorption activity is considerably decreased

endocrine/exocrine glands
• mammary gland regression after removal of pups is delayed (J:162957)
• degree of regression at 72 hours is similar to controls (J:162957)
• mammary gland development is normal at 10 days into lactation (J:162957)
• increase in apoptosis levels of involuting mammary glands is delayed (J:162957)
• elevated milk production (J:162957)
• pups nourished by mutant mothers weigh more than pups nourished by control mothers (J:162957)

integument
• mammary gland regression after removal of pups is delayed (J:162957)
• degree of regression at 72 hours is similar to controls (J:162957)
• mammary gland development is normal at 10 days into lactation (J:162957)
• increase in apoptosis levels of involuting mammary glands is delayed (J:162957)
• elevated milk production (J:162957)
• pups nourished by mutant mothers weigh more than pups nourished by control mothers (J:162957)

cellular
• in vitro differentiation is markedly attenuated

growth/size
• distance between cementoenamel junction and alveolar bone crest is greater than for controls from 6 weeks on (without any bacterial challenge)


Mouse Genome Informatics
hm2
    Nos2tm1Mrl/Nos2tm1Mrl
either: 129S/Sv or B6J.129S7-Nos2tm1Mrl
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
reproductive system
N
• no difference in the number of oocytes released or survival of in vitro fertilized embryos is seen between female mutants and wild-type mice unlike in Nos3tm1Weo female mutants (J:73964)


Mouse Genome Informatics
hm3
    Nos2tm1Mrl/Nos2tm1Mrl
involves: 129S7/SvEvBrd
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

growth/size
• body weight is about 15% greater than controls

immune system
• blood eosinophil numbers increase much less in OVA treated mice than in OVA treated controls
• numbers of eosinophils in bronchoalveolar lavage fluid half of control numbers in OVA treated mice
• PGE2 production increase in response to stimulation with IFNgamma and LPS is considerably more modest than for controls
• higher IFN gamma secretion by lung and splenic T cells
• anesthetized mutants are substantially protected from septic shock induced by endotoxic lipopolysaccharide (LPS), however unanesthetized mutants exhibit as much LPS-induced liver damage as wild-type mice
• non-eosinophilic inflammatory responses are somewhat enhanced
• mutants succumb to lower doses of Listeria monocytogenes than wild-type mice, with approximate 100-fold greater bacterial burdens in liver and spleen

cardiovascular system
N
• unlike in mice null for Nos3 no significant abnormalities in hypoxic pulmonary vasoconstriction or vasodilation in response to bradykinin are detected (J:57624)
• more vascularization of the retinal surface than seen in controls after 5 days of oxygen exposure followed by 120 hours of hypoxia
• increase in right ventricle systolic pressure in mice exposed to chronic mild hypoxia compared to similarly treated wild-type controls

homeostasis/metabolism
• reactive nitrogen intermediates do not increase in OVA treated mice as they do in OVA treated controls
• significantly increased amounts of PxP2 are derived from platelet aggregation
• considerably reduced amounts of PGE2 are excreted in urine
• also considerably reduced amounts of PGF2-like F2-isoprostanes excreted
• callus cross-sectional area increased relative to controls during healing of fractured femora
• increased torsional failure during healing
• wound closure is significantly delayed

vision/eye
• more vascularization of the retinal surface than seen in controls after 5 days of oxygen exposure followed by 120 hours of hypoxia
• intravitreal neovascularization is considerably less than in controls after 5 days of oxygen exposure followed by 120 hours of hypoxia

skeleton
• callus cross-sectional area increased relative to controls during healing of fractured femora
• increased torsional failure during healing
• bone volume/trabecular volume is increased

renal/urinary system
• considerably reduced amounts of PGE2 are excreted in urine
• also considerably reduced amounts of PGF2-like F2-isoprostanes excreted

hematopoietic system
• blood eosinophil numbers increase much less in OVA treated mice than in OVA treated controls
• numbers of eosinophils in bronchoalveolar lavage fluid half of control numbers in OVA treated mice
• PGE2 production increase in response to stimulation with IFNgamma and LPS is considerably more modest than for controls
• significantly increased amounts of PxP2 are derived from platelet aggregation


Mouse Genome Informatics
hm4
    Nos2tm1Mrl/Nos2tm1Mrl
involves: 129S7/SvEvBrd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• the large arteries of the uterus during pregnancy have thickened arterial walls and smaller lumina (J:78274)
• found in about 35% of homozygotes
• total ventricle weights are greater than controls for males only
• islet blood flow under basal conditions is increased
• relative to controls
• streptozotocin induced diabetes for 8 days results in a more modest increase in blood pressure than in similar controls
• slightly increased at 3 months of age but not later
• area of infarction is greater than for controls in non-diabetic mice after ischemia-reperfusion
• reperfusion injury is less in diabetic mice than in diabetic controls

homeostasis/metabolism
N
• normal serum insulin (J:65562)
• obese mice on a high fat diet have normal insulin levels (J:72215)
• area of infarction is greater than for controls in non-diabetic mice after ischemia-reperfusion
• reperfusion injury is less in diabetic mice than in diabetic controls
• slightly elevated levels
• levels 1.7 times normal at 9 months of age
• elevated plasma triglycerides
• slightly reduced at 3 months and tending to decline with age
• resistant to hyperglycemia induced by multiple low doses of streptozotocin
• hyperglycemic in the first 30 minutes of a glucose tolerance test
• return to fasting glucose levels by 90 minutes when controls are still hyperglycemic
• the cyclic changes in estradiol level are abnormal in homozygous mutant females with the peak in estradiol concentration coming later than in 129/SvEv wild-type females
• plasma ACTH levels increase much more modestly after LPS treatment than for controls
• plasma renin activity is increased
• volume of infarction 96 hours after middle cerebral artery occlusion is 28% smaller than controls
• volume of infarction is similar to controls 24 hours after cerebral artery occlusion
• protected from renal ischemia-reperfusion injury as indicated by lower serum creatine levels compared to controls
• less tubular necrosis, tubular structure is almost normal
• better survival rate at 24 hours after surgeries

reproductive system
• the lining of the uterus during pregnancy shows a distinct lack of cellularity in homozygous female mutants compared to wild-type females (J:78274)
• diestrus length is increased in homozygous mutant females compared to 129/SvEv wild-type mice without an increase in total oestrus cycle length (J:89542)
• by mid-gestation homozygous female mutants have significantly fewer viable embryos compared to wild-type females

nervous system
N
• chronic nerve constriction does not lead to breakdown of small myelinated fibers (J:104959)
• volume of infarction 96 hours after middle cerebral artery occlusion is 28% smaller than controls
• volume of infarction is similar to controls 24 hours after cerebral artery occlusion
• moderate breakdown of larger caliber myelinated fibers 5 days after chronic nerve constriction at a time when controls have far fewer surviving fibers
• fiber numbers are declining at 14 days but at a slower rate than for controls
• degenerating myelinated fibers persist longer after nerve crush injury
• no regenerative myelinated sprouts at 21 days when they have begun to appear in controls
• regenerating fibers are smaller in caliber after nerve crush injury
• similar to controls by 6 weeks after nerve crush injury
• nerve fiber regeneration is delayed and new fibers are smaller in diameter after nerve transection

behavior/neurological
• consume 1.6 times as much food as controls on a high fat diet
• motor deficiencies improve between 24 and 96 hours after cerebral artery occlusion unlike controls
• tactile hypersensitivity disappears between 5 and 14 days after the start of chronic nerve constriction while it persists through day 14 in controls
• tactile allodynia observed at 3 weeks when neuropathic pain is diminishing in controls
• thermal hypersensitivity disappears between 5 and 14 days after the start of chronic nerve constriction while it persists through day 14 in controls
• delayed thermal hypersensitivity observed at 3 weeks when neuropathic pain is diminishing in controls

immune system
• low level of islet inflammation as compared to controls when treated with streptozotocin
• islet size is normal
• lower rejection rate of CBA/CaJ cardiac grafts
• lower levels of apoptosis by all measures used

renal/urinary system
• protected from renal ischemia-reperfusion injury as indicated by lower serum creatine levels compared to controls
• less tubular necrosis, tubular structure is almost normal
• better survival rate at 24 hours after surgeries

endocrine/exocrine glands
• low level of islet inflammation as compared to controls when treated with streptozotocin
• islet size is normal

growth/size
• body weight is greater than controls for males only
• experience greater weight gain on a high fat diet

digestive/alimentary system
• do not respond to gastric luminal acid with as great an increase in gastric blood flow as do controls
• vascular resistance is not diminished
• mucus accumulation rate about 25% of controls
• firmly adherent layer of mucus is thinner than in controls

liver/biliary system
• fibrotic changes in the livers of mice on a high fat diet particularly around degenerating hepatocytes and the central vein area
• collagen fraction is higher than in controls when on a high fat diet

integument
• tactile hypersensitivity disappears between 5 and 14 days after the start of chronic nerve constriction while it persists through day 14 in controls
• tactile allodynia observed at 3 weeks when neuropathic pain is diminishing in controls
• thermal hypersensitivity disappears between 5 and 14 days after the start of chronic nerve constriction while it persists through day 14 in controls
• delayed thermal hypersensitivity observed at 3 weeks when neuropathic pain is diminishing in controls


Mouse Genome Informatics
hm5
    Nos2tm1Mrl/Nos2tm1Mrl
involves: 129S7/SvEvBrd * PL/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• levels of experimental autoimmune encephalitis are significantly greater than controls starting 13 days after injection with myelin basic protein
• remission levels are much lower than for controls


Mouse Genome Informatics
cx6
    Apoetm1Unc/Apoetm1Unc
Nos2tm1Mrl/Nos2tm1Mrl

involves: 129P2/OlaHsd * 129S7/SvEvBrd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
N
• no effect on plasma cholesterol, triglycderide, or nitrate levels when compared to Apoetm1Unc controls on any diet tested (J:64566)
• total cholesterol in the aorta is reduced 40% in males and 50% in females
• free cholesterol in the aorta is reduced 40% in males and 50% in females
• cholesterol ester in the aorta is reduced 57% in males and 72% in females

growth/size
• females are slightly heavier than controls
• no weight effect in males

cardiovascular system
• lesions are smaller and flatter
• male lesions are 50% smaller
• female lesions are 30% smaller


Mouse Genome Informatics
cx7
    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
cx8
    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
cx9
    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
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
• plasma osmolality is increased

renal/urinary system

behavior/neurological


Mouse Genome Informatics
cx10
    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
• medial thickening at 5 months
• no vascular lesions in 2 month old males
• significant neointimal formation at 5 months
• significantly increased after i.v. glucose
• elevated plasma triglycerides


Mouse Genome Informatics
cx11
    Nos2tm1Mrl/Nos2tm1Mrl
Tg(Myh6-Tnf)1.6Amf/?

involves: 129S7/SvEvBrd * C57BL/6 * FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• isoproterenol improved fractional shortening relative to transgenic mice with Nos2 intact
• isoproterenol improved left ventricular pressure development relative to transgenic mice with Nos2 intact

muscle
• isoproterenol improved fractional shortening relative to transgenic mice with Nos2 intact


Mouse Genome Informatics
cx12
    Faslpr/Faslpr
Nos2tm1Mrl/Nos2tm1Mrl

involves: 129S7/SvEvBrd * MRL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
renal/urinary system
• protein excretion less than controls at 20 weeks of age but not significantly
• excrete very low levels of nitrite/nitrate relative to controls, heterozygotes are intermediate
• serum and urine levels of nitrite/nitrate are similar

homeostasis/metabolism
• serum and urine levels of nitrite/nitrate are similar
• protein excretion less than controls at 20 weeks of age but not significantly
• excrete very low levels of nitrite/nitrate relative to controls, heterozygotes are intermediate
• serum and urine levels of nitrite/nitrate are similar

immune system
N
• vasculitis absent in renal vessels, unlike controls (J:42666)
• anti-DNA levels similar to controls (J:42666)
• IgG1/IgG3 ratio is higher than controls
• significantly reduced rheumatoid factor specific IgG antibodies
• significantly reduced rheumatoid factor specific IgM antibodies

hematopoietic system
• IgG1/IgG3 ratio is higher than controls
• significantly reduced rheumatoid factor specific IgG antibodies
• significantly reduced rheumatoid factor specific IgM antibodies