Phenotypes associated with this allele

• Allele Symbol: Npc2^tm1Plob
• Allele Name: targeted mutation 1, Peter Lobel and David Sleat
• Allele ID: MGI:3044774
• Summary: 6 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Npc2^tm1Plob/Npc2^tm1Plob	C.129S1-Npc2^tm1Plob	MGI:3759831
hm2	Npc2^tm1Plob/Npc2^tm1Plob	involves: 129S1/Sv	MGI:3044884
hm3	Npc2^tm1Plob/Npc2^tm1Plob	involves: 129S1/Sv * BALB/c	MGI:5538404
hm4	Npc2^tm1Plob/Npc2^tm1Plob	involves: 129S1/Sv * BALB/c * C57BL/6	MGI:3044881
hm5	Npc2^tm1Plob/Npc2^tm1Plob	involves: 129S1/Sv * C57BL/6	MGI:3044883
cx6	Npc1^m1N/Npc1^m1N Npc2^tm1Plob/Npc2^tm1Plob	involves: 129S1/Sv * BALB/c * C57BL/6	MGI:3044885

Genotype
MGI:3759831

hm1

• Allelic Composition: Npc2^tm1Plob/Npc2^tm1Plob
• Genetic Background: C.129S1-Npc2^tm1Plob

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

immune system

decreased NK cell number ( J:125609 )

• mice have reduced numbers of Valpha14 natural killer T cells compared to wild-type mice as determined by staining with the CD1d-alphaGalCer tetramer

• the number of CD1d-alphaGalCer^high CD44^intermediate NK cells is reduced to 2% of the levels found in wild-type mice and persists over time

• the number of CD1d-alphaGalCer^intermediate CD44^high NK cells is reduced to 25% of the levels found in wild-type mice but recovered to wild-type levels by week 12

• however, mice have normal numbers of CD4, CD8 and B cells

abnormal NK cell physiology ( J:125609 )

• remaining NK cells fail to produce or induce the production of interferon-gamma with either lipids or 2 ug of alphaGalCer as do wild-type

• however, some NK cell expansion can observed at day 6 after alphaGalCer stimulation

abnormal T cell physiology ( J:125609 )

• thymocytes fail to activate the production of IL-2 from Valpha14-DN32.D3 cells in an in vitro assay and the activation of TCB11 cells is reduced by 50% compared to activation levels produced by wild-type thymocytes

• stimulation of DN23.D3 cells by thymocytes or splenocytes pulsed with alphaGalCer, an NK cell agonist, is reduced compared to stimulation by wild-type thymocytes and splenocytes and processing or presenting of the Galalpha1-2GalCer is abolished

• unlike in wild-type cells, splenocytes only present iGb3 at the highest concentration used to DN32.D3 cells in an in vitro assay

• however, thymocytes can activate non-Valpha14 NK cells and presentation of MHC class II-restricted proteins such as ovalbumin is normal

cellular

abnormal lysosome morphology ( J:125609 )

• fibroblasts, splenocytes and bone marrow derived cells contain larger lysosomal compartments compared to those found in wild-type cells

• however, intracellular trafficking is normal

hematopoietic system

decreased NK cell number ( J:125609 )

• mice have reduced numbers of Valpha14 natural killer T cells compared to wild-type mice as determined by staining with the CD1d-alphaGalCer tetramer

• the number of CD1d-alphaGalCer^high CD44^intermediate NK cells is reduced to 2% of the levels found in wild-type mice and persists over time

• the number of CD1d-alphaGalCer^intermediate CD44^high NK cells is reduced to 25% of the levels found in wild-type mice but recovered to wild-type levels by week 12

• however, mice have normal numbers of CD4, CD8 and B cells

abnormal NK cell physiology ( J:125609 )

• remaining NK cells fail to produce or induce the production of interferon-gamma with either lipids or 2 ug of alphaGalCer as do wild-type

• however, some NK cell expansion can observed at day 6 after alphaGalCer stimulation

abnormal T cell physiology ( J:125609 )

• thymocytes fail to activate the production of IL-2 from Valpha14-DN32.D3 cells in an in vitro assay and the activation of TCB11 cells is reduced by 50% compared to activation levels produced by wild-type thymocytes

• stimulation of DN23.D3 cells by thymocytes or splenocytes pulsed with alphaGalCer, an NK cell agonist, is reduced compared to stimulation by wild-type thymocytes and splenocytes and processing or presenting of the Galalpha1-2GalCer is abolished

• unlike in wild-type cells, splenocytes only present iGb3 at the highest concentration used to DN32.D3 cells in an in vitro assay

• however, thymocytes can activate non-Valpha14 NK cells and presentation of MHC class II-restricted proteins such as ovalbumin is normal

Genotype
MGI:3044884

hm2

• Allelic Composition: Npc2^tm1Plob/Npc2^tm1Plob
• Genetic Background: involves: 129S1/Sv

mortality/aging

premature death ( J:89617 )

• all mice on a 129S1/Sv genetic background had died by ~90 days of age

Genotype
MGI:5538404

hm3

• Allelic Composition: Npc2^tm1Plob/Npc2^tm1Plob
• Genetic Background: involves: 129S1/Sv * BALB/c

growth/size/body

decreased body weight ( J:204311 )

increased lung weight ( J:204311 )

• lung weight as a % of total body weight is higher

respiratory system

abnormal lung morphology ( J:204311 )

• lungs contain 'nests' of vacuolar filled macrophages and enlarged foamy alveolar macrophages

• accumulation of tubular myelin and surfactant aggregates in large airways and large surfactant aggregates next to type II cells or in the alveolar space

• accumulation of surfactant is seen as tight or loosely packed whirls of phospholipid-like surfactant material in focal areas of the alveolar spaces, and as the most common form, string-like surfactant

abnormal lung vasculature morphology ( J:204311 )

• enlarged polymorphonuclear leukocytes or circulating macrophages filled with vacuolar inclusions are seen within lung capillaries

• capillary endothelial cells containing enlarged vacuoles/multivesicular bodies are seen in lungs

increased lung weight ( J:204311 )

• lung weight as a % of total body weight is higher

abnormal alveolar macrophage morphology ( J:204311 )

• alveolar macrophages are enlarged and vacuole-filled, some with concentric multilamellar electron dense surfactant-like materials

• alveolar macrophages are laden with free cholesterol with many large, foamy cells; phospholipid levels are elevated 2-fold and cholesterol levels are elevated 8-fold in alveolar macrophage

increased lung cholesterol level ( J:204311 )

• increase in cholesterol content in the lungs

• 35-fold elevation of cholesterol levels of branchoalveolar lavage

• 7.9-fold increase in cholesterol levels in lamellar bodies

pulmonary alveolar proteinosis ( J:204311 )

• proteinaceous-like material in the alveolar space

abnormal type II pneumocyte morphology ( J:204311 )

• alveolar type II cells have many autophagosomes

increased alveolar lamellar body number ( J:204311 )

• alveolar type II cells exhibit 65% more lamellar bodies than wild-type cells

small alveolar lamellar bodies ( J:204311 )

• alveolar type II cell lamellar bodies are smaller compared to wild-type mice

thick pulmonary interalveolar septum ( J:204311 )

• increase in alveolar septum thickness

abnormal surfactant composition ( J:204311 )

• increase in surfactant phospholipid levels

hematopoietic system

abnormal alveolar macrophage morphology ( J:204311 )

• alveolar macrophages are enlarged and vacuole-filled, some with concentric multilamellar electron dense surfactant-like materials

• alveolar macrophages are laden with free cholesterol with many large, foamy cells; phospholipid levels are elevated 2-fold and cholesterol levels are elevated 8-fold in alveolar macrophage

homeostasis/metabolism

abnormal lipid level ( J:204311 )

• elevation in lipid content in the lungs

increased lung cholesterol level ( J:204311 )

• increase in cholesterol content in the lungs

• 35-fold elevation of cholesterol levels of branchoalveolar lavage

• 7.9-fold increase in cholesterol levels in lamellar bodies

abnormal phospholipid level ( J:204311 )

• increase in phospholipid content in the lungs

• 3-fold elevation of phospholipid levels of bronchoalveolar lavage

• 2- to 2.8-fold increase in phospholipid levels in lamellar bodies

lipidosis ( J:204311 )

• lungs exhibit severe surfactant accumulation, indicating alveolar lipidosis

pulmonary alveolar proteinosis ( J:204311 )

• proteinaceous-like material in the alveolar space

immune system

abnormal alveolar macrophage morphology ( J:204311 )

• alveolar macrophages are enlarged and vacuole-filled, some with concentric multilamellar electron dense surfactant-like materials

• alveolar macrophages are laden with free cholesterol with many large, foamy cells; phospholipid levels are elevated 2-fold and cholesterol levels are elevated 8-fold in alveolar macrophage

cardiovascular system

abnormal lung vasculature morphology ( J:204311 )

• enlarged polymorphonuclear leukocytes or circulating macrophages filled with vacuolar inclusions are seen within lung capillaries

• capillary endothelial cells containing enlarged vacuoles/multivesicular bodies are seen in lungs

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Niemann-Pick disease		DOID:14504		J:204311

Genotype
MGI:3044881

hm4

• Allelic Composition: Npc2^tm1Plob/Npc2^tm1Plob
• Genetic Background: involves: 129S1/Sv * BALB/c * C57BL/6

Neurodegenerative changes affecting cerebullar Purkinje cells of Npc1^m1N/Npc1^m1N, Npc2^tm1Plob/Npc2^tm1Plob, and double homozygous mice for Npc1^m1N and Npc2^tm1Plob

mortality/aging

premature death ( J:89617 )

• all mice on a genetic background involving 129S1/Sv, BALB/c, C57BL/6 had died by ~130 days of age

behavior/neurological

tremors ( J:89617 )

• continuous tremor first detected at ~55 days of age

abnormal locomotor behavior ( J:89617 )

• following onset of tremors

ataxia ( J:89617 )

• following onset of tremors

growth/size/body

weight loss ( J:89617 )

• mice grew normally until ~55 days of age when they began to lose weight

• later onset and less progressive than in Npc1^m1N homozygotes

homeostasis/metabolism

abnormal lipid homeostasis ( J:89617 )

• cholesterol and other lipid accumulation in the liver at 50 days of age with an ~17 fold increase in plant sterols and marked elevations of sphingomyelin, lyso(bis)phosphatidic acid, gangliosides GM2 and GM3, glucosylceramide, lactosylceramide, and asialo-GM2

• lipid accumulation in the brain at 50 days was largely limited to glycolipids with 11 to 15 fold increases in glucosylceramide, lactosylceramide, and asialo-GM2

• galactosylceramide levels were reduced in the brain, reflecting a general loss of myelin lipids

increased liver cholesterol level ( J:89617 )

• about a 6 fold increase in total cholesterol accumulation in the liver at 28 days of age

• about a 10 fold increase in total cholesterol accumulation in the liver at 50 days of age

• no increase in overall cholesterol levels in the brain, putatively due to compensatory losses due to demyelination, neuronal death, and possible imbalance between neuronal cell bodies and distal axons

• on the cellular level in the brain, unesterified cholesterol was stored in neurons within the neocortex, dentate gyrus, hippocampus, and cerebellum

nervous system

Purkinje cell degeneration ( J:89617 )

• similar progressive degeneration of loss as in Npc1^m1 homozygotes, but later onset

decreased Purkinje cell number ( J:89617 )

liver/biliary system

increased liver cholesterol level ( J:89617 )

• about a 6 fold increase in total cholesterol accumulation in the liver at 28 days of age

• about a 10 fold increase in total cholesterol accumulation in the liver at 50 days of age

• no increase in overall cholesterol levels in the brain, putatively due to compensatory losses due to demyelination, neuronal death, and possible imbalance between neuronal cell bodies and distal axons

• on the cellular level in the brain, unesterified cholesterol was stored in neurons within the neocortex, dentate gyrus, hippocampus, and cerebellum

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Niemann-Pick disease		DOID:14504		J:89617

Genotype
MGI:3044883

hm5

• Allelic Composition: Npc2^tm1Plob/Npc2^tm1Plob
• Genetic Background: involves: 129S1/Sv * C57BL/6

mortality/aging

premature death ( J:89617 )

• all mice on a genetic background involving 129S1/Sv and C57BL/6 had died by ~120 days of age

hematopoietic system

decreased NK cell number ( J:125609 )

immune system

decreased NK cell number ( J:125609 )

Genotype
MGI:3044885

cx6

• Allelic Composition: Npc1^m1N/Npc1^m1N; Npc2^tm1Plob/Npc2^tm1Plob
• Genetic Background: involves: 129S1/Sv * BALB/c * C57BL/6

Neurodegenerative changes affecting cerebullar Purkinje cells of Npc1^m1N/Npc1^m1N, Npc2^tm1Plob/Npc2^tm1Plob, and double homozygous mice for Npc1^m1N and Npc2^tm1Plob

mortality/aging

premature death ( J:89617 )

• all mice on a genetic background involving 129S1/Sv, BALB/c, C57BL/6 had died by ~130 days of age

growth/size/body

weight loss ( J:89617 )

homeostasis/metabolism

abnormal lipid homeostasis ( J:89617 )

• cholesterol and other lipid accumulation in the liver at 50 days of age with an ~17 fold increase in plant sterols and marked elevations of sphingomyelin, lyso(bis)phosphatidic acid, gangliosides GM2 and GM3, glucosylceramide, lactosylceramide, and asialo-GM2

• lipid accumulation in the brain at 50 days was largely limited to glycolipids with 11 to 15 fold increases in glucosylceramide, lactosylceramide, and asialo-GM2

• galactosylceramide levels were reduced in the brain, reflecting a general loss of myelin lipids

increased liver cholesterol level ( J:89617 )

• about a 6 fold increase in total cholesterol accumulation in the liver at 28 days of age

• about a 10 fold increase in total cholesterol accumulation in the liver at 50 days of age

• no increase in overall cholesterol levels in the brain, putatively due to compensatory losses due to demyelination, neuronal death, and possible imbalance between neuronal cell bodies and distal axons

• on the cellular level in the brain, unesterified cholesterol was stored in neurons within the neocortex, dentate gyrus, hippocampus, and cerebellum

nervous system

Purkinje cell degeneration ( J:89617 )

• similar progressive degeneration of loss as in Npc1^m1 homozygotes

decreased Purkinje cell number ( J:89617 )

liver/biliary system

increased liver cholesterol level ( J:89617 )

• about a 6 fold increase in total cholesterol accumulation in the liver at 28 days of age

• about a 10 fold increase in total cholesterol accumulation in the liver at 50 days of age

• no increase in overall cholesterol levels in the brain, putatively due to compensatory losses due to demyelination, neuronal death, and possible imbalance between neuronal cell bodies and distal axons

• on the cellular level in the brain, unesterified cholesterol was stored in neurons within the neocortex, dentate gyrus, hippocampus, and cerebellum

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Niemann-Pick disease		DOID:14504		J:89617