Mouse Genome Informatics
cn1
    Lrp1tm2Her/Lrp1tm2Her
involves: 129S7/SvEvBrd
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
liver/biliary system
• impaired ability to clear 125I-labeled alpha2-macroglobulin from the plasma after adenoviral cre injection into the liver

homeostasis/metabolism
N
• unlike in double mutant mice that are also null for Ldlr , adenoviral cre infection does not alter circulating apolipoprotein levels or the plasma cholesterol profile (J:67929)


Mouse Genome Informatics
cn2
    Lrp1tm2Her/Lrp1tm2Her
Tg(Tagln-cre)1Her/0

B6.Cg-Lrp1tm2Her Tg(Tagln-cre)1Her
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• medial thickness is doubled with an increase in the number of cell nuclei
• increase in the number of disruptions of the elastic layers
• freshly isolated cells are more epithelioid shaped compared to the spindled shaped cells from control mice
• alpha-actin filaments are less abundant and often disrupted in quiescent smooth muscle cells
• aortic smooth muscle cells challenged with PDGF-bb display more rapid alpha-actin filament disassembly and fillapodial extension and enhanced proliferation and migration compared to controls
• cultured aortic smooth muscle cells show enhanced serum induced cell growth
• aortic rings mice fail to reach the 50% level of force generation at any concentration of KCl and phenylephrine tested
• increase in neointimal formation and prolonged neointimal hyperplasia following endothelial denudation of carotid arteries

homeostasis/metabolism
• increase in neointimal formation and prolonged neointimal hyperplasia following endothelial denudation of carotid arteries

muscle
• freshly isolated cells are more epithelioid shaped compared to the spindled shaped cells from control mice
• alpha-actin filaments are less abundant and often disrupted in quiescent smooth muscle cells
• aortic smooth muscle cells challenged with PDGF-bb display more rapid alpha-actin filament disassembly and fillapodial extension and enhanced proliferation and migration compared to controls
• cultured aortic smooth muscle cells show enhanced serum induced cell growth
• aortic rings mice fail to reach the 50% level of force generation at any concentration of KCl and phenylephrine tested


Mouse Genome Informatics
cn3
    Apoetm1Lmh/Apoetm1Lmh
Ldlrtm1Her/Ldlrtm1Her
Lrp1tm2Her/Lrp1tm2Her
Lyz2tm1(cre)Ifo/Lyz2+

involves: 129P2/OlaHsd * 129S7/SvEvBrd
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• the total macrophage and collagen lesion contents are increased
• the percentage (normalized for lesion size) of collagen in lesions is increased; however, the percentages of macrophages and smooth muscle cells in the lesions are similar
• total atherosclerotic lesion area and the proportion of advanced lesions are significantly increased compared to mutant mice expressing Lrp1


Mouse Genome Informatics
cn4
    Ldlrtm1Her/Ldlrtm1Her
Lrp1tm2Her/Lrp1tm2Her
Lyz2tm1(cre)Ifo/Lyz2+

involves: 129P2/OlaHsd * 129S7/SvEvBrd
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• impaired ability to internalize targets coated with LRP ligands
• however, phagocytosis of apoptotic cells in serum free conditions is similar to controls

hematopoietic system
• impaired ability to internalize targets coated with LRP ligands
• however, phagocytosis of apoptotic cells in serum free conditions is similar to controls


Mouse Genome Informatics
cn5
    Ldlrtm1Her/Ldlrtm1Her
Lrp1tm2Her/Lrp1tm2Her
Lyz2tm1(cre)Ifo/Lyz2+

involves: 129P2/OlaHsd * 129S7/SvEvBrd * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• significant decrease in the number of activated glial cells in ischemic tissue after transient middle cerebral artery occlusion
• significant decrease in the number of activated glial cells in ischemic tissue after transient middle cerebral artery occlusion
• significant reduction in the accumulation of nitrotyrosine in the ischemic tissue
• treatment with PLAT fails to restore nitrotyrosine accumulation unlike in mice null for Plat
• 24 hours after transient middle cerebral artery occlusion

homeostasis/metabolism
• significant decrease in the number of activated glial cells in ischemic tissue after transient middle cerebral artery occlusion
• significant reduction in the accumulation of nitrotyrosine in the ischemic tissue
• treatment with PLAT fails to restore nitrotyrosine accumulation unlike in mice null for Plat
• 24 hours after transient middle cerebral artery occlusion

immune system
• significant decrease in the number of activated glial cells in ischemic tissue after transient middle cerebral artery occlusion

hematopoietic system
• significant decrease in the number of activated glial cells in ischemic tissue after transient middle cerebral artery occlusion


Mouse Genome Informatics
cn6
    Ldlrtm1Her/Ldlrtm1Her
Lrp1tm2Her/Lrp1tm2Her

involves: 129S7/SvEvBrd
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• after adenoviral cre infection
• after adenoviral cre infection, concentrations of apoB48 are dramatically increased
• this increase is primarily responsible for the increase in plasma cholesterol and triglyceride levels
• slightly increased after adenoviral cre infection
• after adenoviral cre infection, the total cholesterol profile is dramatically changed
• increase in total plasma cholesterol levels after adenoviral cre infection
• large increase of plasma lipoproteins in the LDL size range after adenoviral cre infection
• large increase of plasma lipoproteins in the chylomicron remnant/VLDL size range after adenoviral cre infection


Mouse Genome Informatics
cn7
    Lrp1tm2Her/Lrp1tm2Her
Tg(Camk2a-cre)T29-1Stl/0

involves: 129S7/SvEvBrd * BALB/c * C57BL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• decrease in spine densities of apical oblique and basal shaft dendrites of pyramidal neurons in the cortex and in the CA1 region of the hippocampus at 18 months but not at 12 months of age
• expression analysis indicates an age dependent decrease in synaptic density
• significantly lower levels of sulfatide, galactosylceramide, cholesterol and triglyceride in the cortex of the brain at 12 months of age
• amyloid-beta levels are decreased in the hippocampus at 18 months of age, indicating that the neurodegeneration likely occurs by an amyloid-beta independent mechanism
• increase in reactive astrocytes and microglial activation in the CA1 region of the hippocampus and in the dentate gyrus but not in the CA3 region of the hippocampus at 18 months of age
• severely reduced in hippocampal slices at 18 months of age
• significant increase in apoptotic cells in the cortex and hippocampus at 24 months but not at 18 months of age

behavior/neurological
• exhibit significantly less freezing time than controls at 18 months of age
• exhibit significantly less freezing time than controls at 18 months of age
• develops by 13 months of age
• at 18 months of age
• in an open field test at 18 months of age

homeostasis/metabolism
• significantly lower levels of sulfatide and galactosylceramide in the cortex of the brain at 12 months of age
• in the cortex of the brain at 12 months of age
• in the cortex of the brain at 12 months of age

immune system
• increase in reactive astrocytes and microglial activation in the CA1 region of the hippocampus and in the dentate gyrus but not in the CA3 region of the hippocampus at 18 months of age

Mouse Models of Human Disease
OMIM IDRef(s)
Alzheimer Disease; AD 104300 J:167724


Mouse Genome Informatics
cn8
    Lrp1tm2Her/Lrp1tm2Her
Tg(APP695)3Dbo/0
Tg(PSEN1)5Dbo/0
Tg(Tagln-cre)1Her/0

involves: 129S7/SvEvBrd * C3H/HeJ * C57BL/6 * C57BL/6J * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• amyloid beta deposition is seen in cortical vessels as cerebral amyloid angiopathy
• activation of astrocytes is enhanced compared to controls with only Tg(PSEN1)5Dbo and Tg(APP69ff5)3Dbo at 1 year of age
• amyloid beta deposition in the brains is higher than in controls with only Tg(PSEN1)5Dbo and Tg(APP69ff5)3Dbo at 13-14 months of age
• amyloid beta deposition is seen in the cortical parenchyma and in cortical vessels as cerebral amyloid angiopathy
• concentrations of insoluble amyloid beta40 and amyloid beta42 is higher than in controls at 13-14 months of age but not at 3 months
• despite the increase in amyloid beta deposition, APP processing and levels of amyloid beta degrading enzymes are normal, indicating that the increase is due to a disturbance of lysosomal-mediated amyloid beta clearance

other phenotype
• amyloid beta deposition is seen in cortical vessels as cerebral amyloid angiopathy
• amyloid beta deposition in the brains is higher than in controls with only Tg(PSEN1)5Dbo and Tg(APP69ff5)3Dbo at 13-14 months of age
• amyloid beta deposition is seen in the cortical parenchyma and in cortical vessels as cerebral amyloid angiopathy
• concentrations of insoluble amyloid beta40 and amyloid beta42 is higher than in controls at 13-14 months of age but not at 3 months
• despite the increase in amyloid beta deposition, APP processing and levels of amyloid beta degrading enzymes are normal, indicating that the increase is due to a disturbance of lysosomal-mediated amyloid beta clearance


Mouse Genome Informatics
cn9
    Lrp1tm2Her/Lrp1tm2Her
Tg(Fabp4-cre)1Rev/0

involves: 129S7/SvEvBrd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
adipose tissue
• reduced by more than 65% compared to controls
• difference in body weight is entirely due to the decrease in fat mass
• due to a macroscopically obvious decrease in the interscapular and epididymal fat pads
• increase in fat mass loss when fasted for 24 h
• dramatic decrease in uptake of lipids by adipocytes
• decrease is more dramatic in brown adipose tissue compared to white adipose tissue

growth/size
• increase in fat mass loss when fasted for 24 h
• difference in body weight is entirely due to the decrease in fat mass
• due to a macroscopically obvious decrease in the interscapular and epididymal fat pads
• when placed on a high fat diet
• increase in fat mass loss when fasted for 24 h

homeostasis/metabolism
N
• no difference in respiratory quotients is detected compared to controls (J:127398)
• core temperature decreases faster when the ambient temperature is lowered compared to similarly exposed controls
• consistent with the decrease in total body fat amount
• at 22 degrees C core temperature is similar to controls but surface temperature is reduced
• the difference in surface temperature compared to controls becomes more pronounced at 4 degrees C
• behavioral signs (shivering and trunk curl) indicate impaired ability to maintain body temperature
• on normal chow and high fat diets
• when placed on a high fat diet
• markedly lower fasting glucose levels
• fasting glucose levels do not increase even after 16 weeks on a high fat diet
• markedly lower fasting insulin levels
• fasting insulin levels do not increase even after 16 weeks on a high fat diet
• results indicate that skeletal muscle is responsible for the elevated plasma glucose clearance
• postprandial lipid clearance from the circulation in response to a bolus fat load is markedly delayed
• markedly lower fasting non-esterified fatty acids levels

behavior/neurological
• despite weighing less, mice consume more food compared to controls
• body surface reduction by coiling up that is visible at room temperature (22 degrees C) but becomes more pronounced at 4 degrees C

muscle
• enhanced skeletal muscle glucose uptake consistent with the increased muscle activity is seen

liver/biliary system


Mouse Genome Informatics
cn10
    Lrp1tm2Her/Lrp1tm2Her
Tg(Syn1-cre)671Jxm/0

involves: 129S7/SvEvBrd * C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• die around 9 months of age

reproductive system
• greatly reduced fertility

behavior/neurological
• adults eat more compared to wild-type controls
• a constant muscle tremor develops by 3 weeks of age
• pronounced hind limb weakness, unable to stand on their hind legs
• develop dystonic posturing over time
• over time increased plantar flexion of the feet occurs, with asymmetric involvement in some mice
• general hyperactivity combined with increased voluntary movement, detectable by 3 weeks of age
• waddling gait
• step width increases in relation to step length

skeleton
• increased thoracic kyphosis develops over time

growth/size
• adults are leaner than wild-type controls
• initially similar in size and weight to wild-type controls but gradually fall behind in their growth rate

adipose tissue
• adults are leaner than wild-type controls

homeostasis/metabolism

nervous system
N
• no histological defects in brain morphology are detected (J:93329)
• electroencephalographic and electromyographic studies confirmed the tremor but did not detect any abnormalities in neuro- or neuromuscular transmission (J:93329)
• no abnormalities in hippocampal long term potentiation are detected (J:93329)


Mouse Genome Informatics
cn11
    Ldlrtm1Her/Ldlrtm1Her
Lrp1tm2Her/Lrp1tm2Her
Vldlrtm1Her/Vldlrtm1Her
Tg(Mx1-cre)29-4Her/0

involves: 129S7/SvEvBrd * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• mice show significantly elevated FVIII (Factor 8), similar to Ldlr/Lrp double mutants


Mouse Genome Informatics
cn12
    Lrp1tm2Her/Lrp1tm2Her
Tg(Mx1-cre)29-4Her/0

involves: 129S7/SvEvBrd * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• mice show slightly elevated FVIII (Factor 8) and VWF (von Willebrand factor) levels, by 1.6- and 1.3-fold respectively; tissue plasminogen activator (t-PA) levels are increased by2.4 fold relative to controls


Mouse Genome Informatics
cn13
    Ldlrtm1Her/Ldlrtm1Her
Lrp1tm2Her/Lrp1tm2Her
Tg(Mx1-cre)29-4Her/0

involves: 129S7/SvEvBrd * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• levels are significantly increased (>10-fold) compared to controls
• levels are significantly increased (>10-fold) compared to controls
• mice show significantly elevated FVIII (Factor 8) and VWF (von Willebrand factor) levels, by 4.2- and 3.3-fold respectively


Mouse Genome Informatics
cn14
    Lrp1tm2Her/Lrp1tm2Her
Tg(Mx1-cre)29-4Her/0

involves: 129S7/SvEvBrd * C57BL/6J * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• clearance of Factor VII from the plasma is slower in pIpC treated mice
• increase in Factor VIII and von Willebrand factor levels by 10 days after pIpC treatment
• increase in levels persists for at least 6 weeks after pIpC treatment
• the ratio of Factor VIII to von Willebrand factor is also increased following pIpC treatment

liver/biliary system
• clearance of Factor VII from the plasma is slower in pIpC treated mice


Mouse Genome Informatics
cn15
    Apoetm1Lmh/Apoetm1Lmh
Ldlrtm1Her/Ldlrtm1Her
Lrp1tm2Her/Lrp1tm2Her
Tg(Mx1-cre)29-4Her/0

involves: 129S7/SvEvBrd * C57BL/6J * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• following pIpC treatment, plasma cholesterol level is lower compared to mutant mice wild-type for Lrp1
• following pIpC treatment, plasma LDL cholesterol level is lower compared to mutant mice wild-type for Lrp1
• following pIpC treatment, plasma VLDL cholesterol level is lower compared to mutant mice wild-type for Lrp1
• following pIpC treatment, plasma triglyceride level is lower compared to mutant mice wild-type for Lrp1
• increase in Factor VIII, von Willebrand factor, and tissue type plasminogen activator levels by 4 weeks after pIpC treatment (J:90547)
• mice show elevated FVIII (Factor 8) levels (J:117317)
• following pIpC treatment, plasma lipoprotein lipase level is higher compared to mutant mice wild-type for Lrp1
• however, no increase in lipoprotein lipase activity is detected

cardiovascular system
• increase in lesion size in pIpC treated mice compared to untreated controls
• however, no change in lesion composition is detected


Mouse Genome Informatics
cn16
    Ldlrtm1Her/Ldlrtm1Her
Lrp1tm2Her/Lrp1tm2Her
Tg(Mx1-cre)29-4Her/0

involves: 129S7/SvEvBrd * C57BL/6J * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• increase in total plasma cholesterol levels within 10 days of pIpC injection
• large increase of plasma lipoproteins in the LDL size range within 10 days of pIpC injection
• large increase of plasma lipoproteins in the chylomicron remnant/VLDL size range within 10 days of pIpC injection
• within 10 days of pIpC injection
• within 10 days of pIpC injection, concentrations of apoB48 are dramatically increased
• this increase is primarily responsible for the increase in plasma cholesterol and triglyceride levels


Mouse Genome Informatics
cn17
    Ldlrtm1Her/Ldlrtm1Her
Lrp1tm2Her/Lrp1tm2Her
Tg(Tagln-cre)1Her/0

involves: 129S7/SvEvBrd * C57BL/6J * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• progressive thickening of the aorta wall with age
• thickening is primarily caused by increased smooth muscle cell proliferation
• aortas are consistently distended and dilated
• pronounced atherosclerosis is seen in the aorta
• on a high cholesterol diet
• addition of Gleevec to the diet protects against atherosclerotic lesion formation
• almost complete occlusion of the mesenteric arteries
• increase in vascular smooth muscle cell proliferation

homeostasis/metabolism
N
• no changes in cholesterol or triglyceride levels are detected compared to mice homozygous for Ldlrtm1Her alone (J:82871)

muscle
• increase in vascular smooth muscle cell proliferation