Phenotypes associated with this allele

• Allele Symbol: Nr1h3^tm1.1Gstr
• Allele Name: targeted mutation 1.1, Gertrud Schuster
• Allele ID: MGI:2653344
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Nr1h3^tm1.1Gstr/Nr1h3^tm1.1Gstr	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:2653346
cx2	Nr1h2^tm1.1Gstr/Nr1h2^tm1.1Gstr Nr1h3^tm1.1Gstr/Nr1h3^tm1.1Gstr	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:2653351

Genotype
MGI:2653346

hm1

• Allelic Composition: Nr1h3^tm1.1Gstr/Nr1h3^tm1.1Gstr
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

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

homeostasis/metabolism

abnormal cellular cholesterol metabolism ( J:82096 )

• when mice are fed a diet with 2% cholesterol, levels of 24- and 27-hydroxycholesterol are increased relative to in wild-type mice

increased circulating LDL cholesterol level ( J:82096 )

• when mice are fed a diet with 2% cholesterol, serum cholesterol levels, especially LDL, are increased

increased circulating alanine transaminase level ( J:82096 )

• when mice are fed a diet with 2% cholesterol

increased liver cholesterol level ( J:82096 )

• when mice are fed a diet with 2% cholesterol, hepatic cholesterol levels are increased five-fold compared to two-fold in wild-type

respiratory system

respiratory system phenotype ( J:234268 )

N • mice exhibit normal gross lung morphology at 14 months of age

liver/biliary system

enlarged liver ( J:82096 )

• when mice are fed a diet with 2% cholesterol, liver size is increased

increased liver cholesterol level ( J:82096 )

• when mice are fed a diet with 2% cholesterol, hepatic cholesterol levels are increased five-fold compared to two-fold in wild-type

pale liver ( J:82096 )

• when mice are fed a diet with 2% cholesterol, liver color is pale

cellular

abnormal cellular cholesterol metabolism ( J:82096 )

• when mice are fed a diet with 2% cholesterol, levels of 24- and 27-hydroxycholesterol are increased relative to in wild-type mice

growth/size/body

enlarged liver ( J:82096 )

• when mice are fed a diet with 2% cholesterol, liver size is increased

Genotype
MGI:2653351

cx2

• Allelic Composition: Nr1h2^tm1.1Gstr/Nr1h2^tm1.1Gstr; Nr1h3^tm1.1Gstr/Nr1h3^tm1.1Gstr
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

endocrine/exocrine glands

abnormal neurohypophysis median eminence morphology ( J:81790 )

• by 1 year of age, oil red O staining indicates the presence of lipid-laden cells around the median eminence

mortality/aging

premature death ( J:234268 )

• mice begin to die after 12 months of age, with an overall survival of 16.5 +/- 2.9 months

neoplasm

increased lung squamous cell carcinoma incidence ( J:234268 )

• mice exhibit multiple lesions with a high density of disorganized epithelial cells in the lungs at 14 months of age, with lesions present in the alveolar space and in the lung parenchyma

• marker analysis indicates that lesions are squamous cell lung carcinoma-like lesions involving p63, CK14, Sox2+ and TTF1 and pro-SPC-negative epithelial cells and not adenocarcinomas

nervous system

abnormal brain vasculature morphology ( J:81790 )

• by 1 year of age, oil red O staining shows accumulation of lipid droplets around abnormal microvessels in substantia nigra pars reticularis

• enlarged and distorted brain blood vessels are predominantly observed in the pars reticularis of the substantia nigra and globus pallidus; an increase in both number and size of brain vessels is revealed by H&E staining

• fewer microvessels are affected in the hippocampus and cerebellum, with only a few being abnormal in the cerebral cortex

• although microvessels show normal endothelial cells and tight junctions, pericytes contain lipofuscin, collagen bundles appear thick and disorganized, and astrocytic feet are swollen and contain pale lipid vacuoles and myelin-like inclusions

intracranial hemorrhage ( J:81790 )

• some double homozygotes show evidence of previous hemorrhage in the thalamus, globus pallidus, pontin, and hippocampus

abnormal neurohypophysis median eminence morphology ( J:81790 )

• by 1 year of age, oil red O staining indicates the presence of lipid-laden cells around the median eminence

abnormal brain ventricle morphology ( J:81790 )

• by 1 year of age, oil red O staining indicates the presence of lipid-laden cells around the lateral ventricle, third ventricle, and fourth ventricle

abnormal brain ependyma morphology ( J:81790 )

• ependymal cells, esp. those around the third ventricle and cerebral aqueduct, contain large lipid vacuoles and appear swollen

• no visible space is observed between ependymal cells and choroid epithelial cells

small fourth ventricle ( J:81790 )

• by 1 year of age, the size of the fourth ventricle is decreased but the reduction is not as severe as that observed in the lateral and third ventricles

abnormal lateral ventricle morphology ( J:81790 )

• by 1 year of age, the lateral ventricles are closed and lined with lipid-laden cells

small lateral ventricles ( J:81790 )

• the size of lateral ventricles is significantly reduced with little empty space left relative to wild-type control mice

abnormal choroid plexus morphology ( J:81790 )

• the cytoplasm of choroid plexus epithelial cells is filled with lipid vacuoles, and mitochondria are smaller than normal

• no visible space is observed between ependymal cells and choroid epithelial cells

absent choroid plexus ( J:81790 )

• no choroid plexus and no villi are detected; instead, a pale layer in the lateral ventricle, with an increased number of blood vessels, is observed

abnormal third ventricle morphology ( J:81790 )

• by 1 year of age, the third ventricle is closed due to accumulation of lipid droplets; only a thin split can be observed in some mutant mice

small third ventricle ( J:81790 )

• the dorsal third ventricle is also reduced in size, but the reduction is not as severe as that observed in the lateral and third ventricles

abnormal cerebral aqueduct morphology ( J:81790 )

• by 1 year of age, oil red O staining indicates the presence of lipid-laden cells around the cerebral aqueduct

• the size of the cerebral aqueduct is decreased but the reduction is not as severe as that observed in the lateral and third ventricles

abnormal substantia nigra pars reticulata morphology ( J:81790 )

• aging double homozygotes display cholesterol clefts and foamy cells in the pars reticularis of substantia nigra, as revealed by toluidine blue staining

• a severe destruction by lipid crystal clefts is observed

abnormal astrocyte morphology ( J:81790 )

• as double homozygotes age, perivascular astrocytes accumulate lipid vacuoles and myelin-like or laminar-like structures

astrocytosis ( J:81790 )

• the neuronal deficit is accompanied by a significant increase in the number of astrocytes in the substantia nigra and globus pallidus

abnormal myelin sheath morphology ( J:81790 )

• thin uncompacted myelin sheaths without major dense lines are observed in substantia nigra pars reticularis

decreased neuron number ( J:81790 )

• aging double homozygotes display a decreased number of neurons in the substantia nigra and globus pallidus relative to wild-type littermates

neuron degeneration ( J:81790 )

• many dark-colored neurons are observed around the abnormal brain blood vessels, showing nuclear and cytoplasmic condensation with condensed and packed ribosomes and lipofuscin in the cytoplasm

• the Golgi apparatus is swollen or condensed, and plasma and nuclear membranes are ruffled, whereas mitochondria appear unaffected

abnormal spinal cord central canal morphology ( J:81790 )

• by 1 year of age, the central canal of the spinal cord is reduced in size, but the reduction is not as severe as that observed in the lateral and third ventricles

abnormal myelination ( J:81790 )

• global axon dysmyelination with thin uncompacted myelin sheaths without major dense lines is observed in substantia nigra pars reticularis

homeostasis/metabolism

abnormal lipid homeostasis ( J:81790 )

• aging double homozygotes display lipid accumulation around the blood-CSF barrier, the blood-brain barrier, and specific brain regions including the lateral ventricle, third ventricle, cerebral aqueduct, fourth ventricle, median eminence subfornical organ, and organum vasculosum of the lamina terminalis, as well as the pars reticularis of substantia nigra, globus pallidus, and subthalamic nucleus

• in these regions, lipid-laden cells are observed primarily around the blood vessels

• a marked accumulation of ApoE protein is noted in substantia nigra and cells surrounding the lateral ventricle; ApoE-positive cells are also found around blood vessels in the cerebral cortex

abnormal cholesterol homeostasis ( J:81790 )

• expression of several target genes involved in cholesterol efflux from astrocytes is significantly reduced

abnormal lipid level ( J:234268 )

• mice show progressive lipid accumulation in the lungs, with focal spots along the margin of the lungs at 3 months, lesions that spread from the periphery toward the center at 7 months, and by 14 months, most of the lung is covered by a golden coat of lipid

respiratory system

lung inflammation ( J:234268 )

• 12 month old lungs show lymphoid hyperplasia around vessels and CD3+ inflammatory T cells infiltrating the parenchyma, and large clusters of CD206+ macrophages in alveolar spaces indicating chronic lung inflammation

• myeloperoxidase, a neutrophil marker, is highly expressed in lung macrophages and many cells express inflammatory cytokines IL1-beta and TNF-alpha

abnormal lung morphology ( J:234268 )

• mice show progressive lipid accumulation in the lungs

• by 3 months of age, mice accumulate lipids in the distal parts of the lung close to the pleural surface and over the next 12 months, progressive and massive lipid deposition is seen in type 1 and 2 pneumocytes, in the alveolar wall, and in alveolar macrophages

• massive lipid accumulation is seen in the cells surrounding the hyperplastic epithelial lesions in 14 month old mice and in epithelial cells in the bronchioles

• lipid accumulation in lung is accompanied by loss of Cav-1+ type I pneumocytes, the proliferation and dysplasia of type 2 pneumocytes, and the appearance of pro-SPC negative cuboidal epithelial cells lining the alveoli

increased lung squamous cell carcinoma incidence ( J:234268 )

• mice exhibit multiple lesions with a high density of disorganized epithelial cells in the lungs at 14 months of age, with lesions present in the alveolar space and in the lung parenchyma

• marker analysis indicates that lesions are squamous cell lung carcinoma-like lesions involving p63, CK14, Sox2+ and TTF1 and pro-SPC-negative epithelial cells and not adenocarcinomas

abnormal pulmonary alveolar system morphology ( J:234268 )

• lung shows extensive remodeling of the alveolar regions

abnormal pulmonary alveolar parenchyma morphology ( J:234268 )

• lipofibroblasts show increased size of lipid droplets around the nucleus

abnormal alveolar lamellar body morphology ( J:234268 )

• type 2 pneumocytes show abnormal lamellar bodies

respiratory distress ( J:234268 )

• severe dyspnea

cardiovascular system

abnormal brain vasculature morphology ( J:81790 )

• by 1 year of age, oil red O staining shows accumulation of lipid droplets around abnormal microvessels in substantia nigra pars reticularis

• enlarged and distorted brain blood vessels are predominantly observed in the pars reticularis of the substantia nigra and globus pallidus; an increase in both number and size of brain vessels is revealed by H&E staining

• fewer microvessels are affected in the hippocampus and cerebellum, with only a few being abnormal in the cerebral cortex

• although microvessels show normal endothelial cells and tight junctions, pericytes contain lipofuscin, collagen bundles appear thick and disorganized, and astrocytic feet are swollen and contain pale lipid vacuoles and myelin-like inclusions

intracranial hemorrhage ( J:81790 )

• some double homozygotes show evidence of previous hemorrhage in the thalamus, globus pallidus, pontin, and hippocampus

hematopoietic system

increased macrophage derived foam cell number ( J:81790 , J:234268 )

• aging double homozygotes contain foamy cells in the pars reticularis of substantia nigra, as revealed toluidine blue staining (J:81790)

• foamy cells are filled with lipid remnants; only a few organelles are left (J:81790)

• a few small lipid droplets of less intensity are also observed in the cerebral cortex, hippocampus, cerebellum, and spinal cord (J:81790)

• mice show massive accumulation of foam cells in the lungs (J:234268)

immune system

increased macrophage derived foam cell number ( J:81790 , J:234268 )

• aging double homozygotes contain foamy cells in the pars reticularis of substantia nigra, as revealed toluidine blue staining (J:81790)

• foamy cells are filled with lipid remnants; only a few organelles are left (J:81790)

• a few small lipid droplets of less intensity are also observed in the cerebral cortex, hippocampus, cerebellum, and spinal cord (J:81790)

• mice show massive accumulation of foam cells in the lungs (J:234268)

lung inflammation ( J:234268 )

• 12 month old lungs show lymphoid hyperplasia around vessels and CD3+ inflammatory T cells infiltrating the parenchyma, and large clusters of CD206+ macrophages in alveolar spaces indicating chronic lung inflammation

• myeloperoxidase, a neutrophil marker, is highly expressed in lung macrophages and many cells express inflammatory cytokines IL1-beta and TNF-alpha

cellular

increased macrophage derived foam cell number ( J:81790 , J:234268 )

• aging double homozygotes contain foamy cells in the pars reticularis of substantia nigra, as revealed toluidine blue staining (J:81790)

• foamy cells are filled with lipid remnants; only a few organelles are left (J:81790)

• a few small lipid droplets of less intensity are also observed in the cerebral cortex, hippocampus, cerebellum, and spinal cord (J:81790)

• mice show massive accumulation of foam cells in the lungs (J:234268)

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
lung squamous cell carcinoma		DOID:3907		J:234268