Overview

This knockout allele of the Npc1 (Niemann Pick type C1) gene may be useful in studies of Niemann-Pick Type C disease.

Donating Investigator

Dr. Matthew Scott, Stanford University School of Medicine

Genetic overview

Genetic Background	Generation

Npc1^m1N

Allele Type	Gene Symbol	Gene Name
Spontaneous	Npc1	NPC intracellular cholesterol transporter 1

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Research Applications

Neurobiology Research
Mouse/Human Gene Homologs
Internal/Organ Research
Metabolism Research

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Base Price

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$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

This FVB/NJ congenic model of Niemann-Pick Type C disease was derived from backcrosses of the original Npc1^m1N (Niemann Pick type C1 NIH) spontaneous mutation strain (see Stock No. 003092), on the BALB/cNctr background.

Homozygous mice show reduced levels of myelin in the cerebellum. Astrocytes and microglia proliferate and occupy areas of neuronal loss or degeneration. Weight loss is accompanied by a progressive motor coordination deficit, or ataxia, at least as early as postnatal day 45 (P45). The lifespan of homozygous animals is reduced to a mean of 76 days.

Rescue of NPC1 deficiency can be achieved in a tissue-specific manner through crosses with a tetracycline-inducible tetO-Npc1-YFP transgenic animal (see Stock No. 021065) and an appropriate tTA/rtTA tetracycline-responsive mutant line.

The Npc1^m1N allele is also available on a C57BL/6J congenic background (Stock No. 030097).

Development

824 bp of MaLR retroposon-like DNA replaced 703 bp of wild-type genomic sequence spanning 44 bp of an exon and 659 bp of the downstream intron. The insertion results in premature truncation of the protein deleting 11 out of 13 transmembrane domains. Northern blot analysis revealed marked decrease in gene expression in liver and brain from homozygous mutant animals. This mutation arose spontaneously on the BALB/cNctr inbred background (see Stock No. 003092) and was backcrossed to FVB/NJ for more than 10 generations by the donating laboratory to create a congenic line.

Control Suggestions

Wild-type from the colony
001800 FVB/NJ

Additional Information

Considerations for Choosing Controls

Selected References

Lopez ME; Klein AD; Dimbil UJ; Scott MP. 2011. Anatomically defined neuron-based rescue of neurodegenerative niemann-pick type C disorder. J Neurosci 31(12):4367-78PubMed: 21430138 MGI: J:170312

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Genetics

Npc1^m1N

Allele Symbol: Npc1^m1N

Allele Name	Niemann Pick type C1 NIH
Allele Type	Spontaneous
Allele Synonym(s)	-^npc; CSD; lcsd; lysosomal cholesterol storage disease; nctr; NPC; Npc-; npc^nih; NPC1; NPC1-; Npc1^N; npc1^NIH
Gene Symbol and Name	Npc1, NPC intracellular cholesterol transporter 1
Gene Synonym(s)
Strain of Origin	BALB/c
Chromosome	18
Molecular Note	824 bp of MaLR retroposon-like DNA replaced 703 bp of wild-type genomic sequence spanning 44 bp of an exon and 659 bp of the downstream intron. The insertion results in premature truncation of the protein deleting 11 out of 13 transmembrane domains. Northern blot analysis revealed marked decrease in gene expression in liver and brain from homozygous mutant animals.

Disease/Phenotype

Disease Terms

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

Niemann-Pick disease

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Npc1^m1N related

Neurobiology Research
- Tremor Defects
- Ataxia (Movement) Defects
- Cerebellar Defects
- Metabolic Defects
- Myelination Defects
- Neurodegeneration
- Neuromuscular defects
Mouse/Human Gene Homologs
- Niemann-Pick disease, type C
Metabolism Research
Internal/Organ Research
- Liver Defects
- Spleen Defects

Neurobiology Research
- Tremor Defects
- Myelination Defects
- Metabolic Defects
- Ataxia (Movement) Defects
- Cerebellar Defects
- Neurodegeneration
Internal/Organ Research
- Spleen Defects
- Liver Defects
Mouse/Human Gene Homologs
- Niemann-Pick disease, type C

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Npc1^m1N/Npc1^m1N
involves: BALB/c

adipose tissue phenotype

decreased abdominal fat pad weight
- female homozygotes exhibit reduced abdominal fat deposits relative to wild-type females

reproductive system phenotype

abnormal female reproductive system morphology
- at 7-8 weeks of age, female homozygotes exhibit a thinner reproductive tract than wild-type females

abnormal granulosa cell morphology
- at 7-8 weeks of age, mutant mural granulosa cells exhibit lipid accumulation, as shown by oil-red-O staining

abnormal ovarian follicle morphology
- at 7 weeks of age, mutant ovarian follicles and stromata exhibit lipid accumulation, as shown by oil-red-O staining

abnormal ovarian secretion
- adult mutant ovaries show near absence of 17beta-estradiol (E2) content (2.0 pg) relative to 110-135 pg/ovary in wild-type controls
- expression of two key steroidogenic proteins (StAR and Cyp19) is markedly reduced in mutant ovaries relative to wild-type controls
- Normal - however, exogenous gonadotropin treatment restores expression of both steroidogenic proteins to wild-type levels

abnormal ovary morphology
- at 7-8 weeks of age, the stromata of mutant ovaries contain numerous islands of foamy cells composed of healthy nuclei and vacuolated cytoplasm
- these cell nests are replete with lipid, as shown by oil-red-O staining

abnormal secondary ovarian follicle morphology
- at 7 weeks of age, mutant antral follicles are smaller than the largest follicles found in wild-type controls
- chronic treatment of 8-wk-old female mutants with 17beta-estradiol (E2) increases the number of secondary and large antral follicles, well in excess of that found in untreated mutant ovaries
- exogenous gonadotropin treatment induces development of numerous large antral follicles at 48 hrs in both wild-type and mutant ovaries; however, mutant ovaries display fewer large follicles in response to eCG
- the number of mutant secondary and antral follicles is reduced relative to wild-type controls

abnormal sperm head morphology
- at 60 days of age, aberrant cauda sperm heads are frequentyly observed

abnormal sperm physiology
- 30% of total cyritestin protein is not proteolytically processed on mutant cauda sperm, whereas fertilin beta is processed normally

absent corpus luteum
- at 7-8 weeks of age, no formation of corpora lutea is observed
- injection of hCG after eCG treatment induces formation of corpora lutea in both wild-type and mutant mice; however, less than half the number of corpora lutea are detected in mutant ovaries

absent estrous cycle
- female homozygotes are acyclic

absent mature ovarian follicles
- mutant ovarian follicles fail to mature to the large antral and preovulatory stages

absent sperm flagellum
- at 60 days of age, tailless sperm heads are frequently observed

absent sperm head
- at 60 days of age, headless sperm tails are frequently observed

anovulation
- at 7-8 weeks of age, mutant ovaries display no evidence of ovulation
- exogenous gonadotropin treatment induces ovulation in both wild-type and mutant ovaries; however, mutant ovaries exhibit fewer large follicles in response to eCG and fewer ovulations in response hCG
- mutant ovaries transplanted under wild-type kidney capsules display evidence of ovulation, as shown by the presence of corpora lutea and an extraovarian oocyte

arrest of spermatogenesis
- male homozygotes show a partial arrest of spermatogenesis, with some tubules containing fused spermatogenic cells with more than one nucleus while other tubules appear normal

decreased endometrial gland number
- at 7-8 weeks of age, reduction in the endometrial stroma is associated with a reduction in the convolution of uterine glands

decreased ovary weight
- at 7-8 weeks of age, the average weight of mutant ovaries is 1.1 +/- 0.22 mg vs 4.76 +/- 0.51 mg for wild-type ovaries

endometrium atrophy

female infertility
- female homozygotes are infertile

impaired binding of sperm to zona pellucida
- when zona-intact eggs are used, the in vitro capacity of mutant sperm to bind to the egg zona pellucida is only 14% of the level in wild-type sperm

impaired fertilization
- in vitro, mutant sperm are unable to fertilize cumulus-intact eggs (CIE) and produce two-cell embryos, unlike wild-type sperm which fertilize ~56% of CIE
- mutant sperm are able to bind to zona-free eggs as well as wild-type sperm but fail to fuse with the egg plasma membrane

infertility
- females showed normal oogenesis, but lacked implantation sites after successful plugging

male infertility
- male homozygotes are infertile

oligozoospermia
- at 60 days of age, the total number of mutant cauda sperm is reduced to only ~28% of that in wild-type males

seminiferous tubule degeneration
- some mutant seminiferous tubules exhibit evidence of extensive degeneration

small ovary
- at 7-8 weeks, but not at 3 weeks, of age mutant ovaries are smaller than wild-type

teratozoospermia
- at 60 days of age, male homozygotes show a significantly higher frequency of abnormal cauda sperm morphology than wild-type males (~32% vs ~7%, respectively)

thin endometrium
- at 8 weeks of age, a reduction in endometrial thickness is observed

thin myometrium

thin uterus
- at 7-8 weeks of age, mutant uteri are thinner than wild-type

uterus atrophy
- at 7-8 weeks of age, atrophy of the myometrium, endometrial stroma, and the endometrial epithelium is observed

endocrine/exocrine gland phenotype

abnormal adenohypophysis morphology
- the mutant anterior pituitary displays vacuolated cells, suggestiing low rates of feedback control and increased hormone synthesis and secretion

abnormal granulosa cell morphology
- at 7-8 weeks of age, mutant mural granulosa cells exhibit lipid accumulation, as shown by oil-red-O staining

abnormal ovarian follicle morphology
- at 7 weeks of age, mutant ovarian follicles and stromata exhibit lipid accumulation, as shown by oil-red-O staining

abnormal ovarian secretion
- adult mutant ovaries show near absence of 17beta-estradiol (E2) content (2.0 pg) relative to 110-135 pg/ovary in wild-type controls
- expression of two key steroidogenic proteins (StAR and Cyp19) is markedly reduced in mutant ovaries relative to wild-type controls
- Normal - however, exogenous gonadotropin treatment restores expression of both steroidogenic proteins to wild-type levels

abnormal ovary morphology
- at 7-8 weeks of age, the stromata of mutant ovaries contain numerous islands of foamy cells composed of healthy nuclei and vacuolated cytoplasm
- these cell nests are replete with lipid, as shown by oil-red-O staining

abnormal secondary ovarian follicle morphology
- at 7 weeks of age, mutant antral follicles are smaller than the largest follicles found in wild-type controls
- chronic treatment of 8-wk-old female mutants with 17beta-estradiol (E2) increases the number of secondary and large antral follicles, well in excess of that found in untreated mutant ovaries
- exogenous gonadotropin treatment induces development of numerous large antral follicles at 48 hrs in both wild-type and mutant ovaries; however, mutant ovaries display fewer large follicles in response to eCG
- the number of mutant secondary and antral follicles is reduced relative to wild-type controls

absent corpus luteum
- at 7-8 weeks of age, no formation of corpora lutea is observed
- injection of hCG after eCG treatment induces formation of corpora lutea in both wild-type and mutant mice; however, less than half the number of corpora lutea are detected in mutant ovaries

absent mature ovarian follicles
- mutant ovarian follicles fail to mature to the large antral and preovulatory stages

adenohypophysis hypoplasia
- the mutant anterior pituitary is hypoplastic relative to wild-type

decreased endometrial gland number
- at 7-8 weeks of age, reduction in the endometrial stroma is associated with a reduction in the convolution of uterine glands

decreased lactotroph cell number
- Normal - however, chronic (4-week) treatment with 17beta-estradiol (E2) restores pituitary volume and acidophil numbers to wild-type levels
- the mutant anterior pituitary shows a dramatic reduction in acidophil cell number relative to wild-type

decreased ovary weight
- at 7-8 weeks of age, the average weight of mutant ovaries is 1.1 +/- 0.22 mg vs 4.76 +/- 0.51 mg for wild-type ovaries

seminiferous tubule degeneration
- some mutant seminiferous tubules exhibit evidence of extensive degeneration

small ovary
- at 7-8 weeks, but not at 3 weeks, of age mutant ovaries are smaller than wild-type

respiratory system phenotype

abnormal alveolar lamellar body morphology
- cholesterol and phospholipid accumulation in lamellar bodies of alveolar type II cells

abnormal alveolar macrophage morphology
- 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 6-fold and cholesterol levels are elevated 15-fold in alveolar macrophages

abnormal lung morphology
- lungs contain 'nests' of vacuolar filled macrophages and enlarged foamy alveolar macrophages

abnormal lung vasculature morphology
- capillary endothelial cells containing enlarged vacuoles/multivesicular bodies are seen in the lungs
- enlarged polymorphonuclear leukocytes or circulating macrophages filled with vacuolar inclusions are seen within lung capillaries

abnormal respiratory system physiology
- liposome degradation is reduced by 46% in the lungs

abnormal surfactant composition
- increase in surfactant phospholipid levels

abnormal type II pneumocyte morphology
- alveolar type II cells have many autophagosomes

enlarged alveolar lamellar bodies
- 42% of alveolar type II cell lamellar bodies are enlarged compared to 15% in wild-type mice

increased lung weight
- lung weight as a % of total body weight is higher
- progressive increase in lung weight, beginning at 7 weeks of age

pulmonary alveolar proteinosis
- mild protein accumulation in bronchoalveolar lavage
- proteinaceous-like material in the alveolar space

thick pulmonary interalveolar septum
- thickening of the intra-alveolar septae with a slight enlargement of the airways

behavior/neurological phenotype

abnormal motor capabilities/coordination/movement
- defects beginning at 7 to 8 weeks of age

decreased food intake
- poor food intake, beginning at 7 weeks of age

impaired coordination
- mice exhibit impaired coordination around 40 days of age with coordination worsening as the mice age

growth/size/body region phenotype

decreased body size
- female homozygotes display a smaller stature than wild-type females

decreased body weight
- female homozygotes display a reduced body mass relative to wild-type females

enlarged liver
- hepatomegaly and associated pale liver, presumably due to lipid accumulation

enlarged spleen
- progressive splenomegaly, beginning at 7 weeks of age

increased liver weight
- progressive increase in liver weight, beginning at 7 weeks of age

increased lung weight
- lung weight as a % of total body weight is higher
- progressive increase in lung weight, beginning at 7 weeks of age

weight loss
- beginning at 7 to 8 weeks of age
- mice exhibit weight loss starting at 40 days of age

hematopoietic system phenotype

abnormal alveolar macrophage morphology
- 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 6-fold and cholesterol levels are elevated 15-fold in alveolar macrophages

enlarged spleen
- progressive splenomegaly, beginning at 7 weeks of age

cardiovascular system phenotype

abnormal lung vasculature morphology
- capillary endothelial cells containing enlarged vacuoles/multivesicular bodies are seen in the lungs
- enlarged polymorphonuclear leukocytes or circulating macrophages filled with vacuolar inclusions are seen within lung capillaries

homeostasis/metabolism phenotype

abnormal cellular cholesterol metabolism
- higher rate of turnover although whole body pool is considerably elevated
- rate of cholesterol synthesis is reduced

abnormal lipid level
- elevation in lipid content in the lungs

abnormal phospholipid level
- 2- to 2.8-fold increase in phospholipid levels in lamellar bodies
- 4-fold elevation of phospholipid levels of bronchoalveolar lavage
- increase in phospholipid content in the lungs
- increase in surfactant phospholipid levels

decreased brain cholesterol level
- decreased levels in the brain at 7 weeks of age relative to controls
- mice have decreased levels of total cholesterol in the brain

decreased circulating prolactin level
- female homozygotes show a dramatic reduction in serum prolactin levels relative to wild-type controls

decreased prolactin level
- Normal - however, chronic (4-week) treatment with 17beta-estradiol (E2) dramatically increases the cytoplasmic signal for prolactin, well in excess of that found in wild-type pituitaries
- mutant pituitaries exhibit decreased concentrations of prolactin, consistent with a significant reduction in pituitary prolactin mRNA

increased cholesterol level
- 12-fold elevation of cholesterol levels in branchoalveolar lavage
- 6.8-fold increase in cholesterol levels in lamellar bodies
- elevated in most organs except the brain at 7 weeks of age
- elevated in the brain at 1 day of age
- increase in cholesterol content in the lungs
- mice have increased cholesterol levels in the liver, spleen, intestine and lung

increased circulating cholesterol level
- progressively increasing plasma cholesterol levels

increased circulating follicle stimulating hormone level
- female homozygotes show a 25% increase in serum FSH levels relative to wild-type controls

increased circulating luteinizing hormone level
- female homozygotes show a dramatic increase in serum LH levels relative to wild-type controls
- Normal - in contrast, pituitary expression and circulating levels of GH remain unaffected

lipidosis
- lipid accumulation (including sphingomyelin, glucocerebroside, lactosylceramide, and cholesterol) in various organs including the liver, lung, kidney, thymus, spleen, and brain
- lungs exhibit surfactant accumulation, indicating alveolar lipidosis

pulmonary alveolar proteinosis
- mild protein accumulation in bronchoalveolar lavage
- proteinaceous-like material in the alveolar space

cellular phenotype

abnormal cellular cholesterol metabolism
- higher rate of turnover although whole body pool is considerably elevated
- rate of cholesterol synthesis is reduced

abnormal Golgi apparatus morphology
- Golgi fragmentation is found in neurons of the cerebral cortex, cerebellar Purkinje cells, and brainstem neurons

abnormal sperm head morphology
- at 60 days of age, aberrant cauda sperm heads are frequentyly observed

absent sperm flagellum
- at 60 days of age, tailless sperm heads are frequently observed

absent sperm head
- at 60 days of age, headless sperm tails are frequently observed

oligozoospermia
- at 60 days of age, the total number of mutant cauda sperm is reduced to only ~28% of that in wild-type males

teratozoospermia
- at 60 days of age, male homozygotes show a significantly higher frequency of abnormal cauda sperm morphology than wild-type males (~32% vs ~7%, respectively)

immune system phenotype

abnormal alveolar macrophage morphology
- 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 6-fold and cholesterol levels are elevated 15-fold in alveolar macrophages

enlarged spleen
- progressive splenomegaly, beginning at 7 weeks of age

liver/biliary system phenotype

enlarged liver
- hepatomegaly and associated pale liver, presumably due to lipid accumulation

hepatic steatosis
- massive liver storage of cholesterol in mice on a high fat, 1% cholesterol diet

increased liver weight
- progressive increase in liver weight, beginning at 7 weeks of age

pale liver

mortality/aging

premature death
- ~75 day life span
- mice die between 80 and 100 days of age from neurodegenerative disease

nervous system phenotype

abnormal adenohypophysis morphology
- the mutant anterior pituitary displays vacuolated cells, suggestiing low rates of feedback control and increased hormone synthesis and secretion

abnormal cerebellum anterior vermis morphology
- by P45, Purkinje cell loss was most evident in the anterior cerebellar vermis
- degenerating cells belonged preferentially to the zebrin II-negative subtype

abnormal cerebellum posterior vermis morphology
- at P60, most surviving Purkinje cells were located in the posterior vermis
- by P45, some Purkinje cell loss was evident in the posterior cerebellar vermis

abnormal CNS glial cell morphology
- glial cells in the corpus callosum reduced by 52%

abnormal myelination
- reduced levels of both myelin protein and myelin cholesterol

abnormal neuron morphology
- vacuolated cytoplasmic storage material in all regions of the central nervous system

abnormal Purkinje cell morphology
- axonal swelling by 11 weeks of age

adenohypophysis hypoplasia
- the mutant anterior pituitary is hypoplastic relative to wild-type

decreased brain cholesterol level
- decreased levels in the brain at 7 weeks of age relative to controls
- mice have decreased levels of total cholesterol in the brain

decreased brain weight
- brain weight is lower than in controls mice
- progressive decrease in brain weight, beginning at 7 weeks of age

decreased corpus callosum size
- glial cells reduced by 52%
- reduced in size by 50% at 11 weeks of age

decreased lactotroph cell number
- Normal - however, chronic (4-week) treatment with 17beta-estradiol (E2) restores pituitary volume and acidophil numbers to wild-type levels
- the mutant anterior pituitary shows a dramatic reduction in acidophil cell number relative to wild-type

decreased Purkinje cell number
- earliest cell loss at P45 throughout the cerebellum; cell loss was profound by P60 in the anterior lobe of the cerebellum; no marked loss after P75
- reduction in numbers increases with age
- small reduction in Purkinje cell numbers in the cerebellar hemispheres at 3 weeks of age

Purkinje cell degeneration
- localized axonal swellings, malformations of the dendritic arbor, and accumulation of vesicular storage materials within the cytoplasm

small cerebellum
- cerebellum weight is smaller than controls

Genotype: Npc1^m1N/Npc1^m1N
involves: 129S1/Sv * BALB/c * C57BL/6

growth/size/body region phenotype

weight loss
- earlier onset and faster progression than in Npc2^tm1Plob homozygotes

liver/biliary system phenotype

increased liver cholesterol level
- about a 10 fold increase in total cholesterol accumulation in the liver at 50 days of age
- about a 6 fold increase in total cholesterol accumulation in the liver at 28 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

mortality/aging

premature death
- all mice on a genetic background involving 129S1/Sv, C57BL/6, and BALB/c died by ~120 days of age

nervous system phenotype

Purkinje cell degeneration

homeostasis/metabolism phenotype

abnormal lipid homeostasis
- 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
- galactosylceramide levels were reduced in the brain, reflecting a general loss of myelin lipids
- -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

increased liver cholesterol level
- about a 10 fold increase in total cholesterol accumulation in the liver at 50 days of age
- about a 6 fold increase in total cholesterol accumulation in the liver at 28 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

Genotype: Npc1^m1N/Npc1^m1N
involves: 129S2/SvPas * BALB/c * C57BL/6

mortality/aging

premature death
- lifespan of Npc1-null mice expressing Il6 is modestly reduced compared to double null littermates

Genotype: Npc1^m1N/Npc1^m1N
BALB/cNctr-Npc1/J

behavior/neurological phenotype

ataxia
- first observed as a lateral displacement of each rear foot at 7 weeks of age

decreased grip strength
- first observed at 9 weeks of age

impaired coordination
- decrease in motor capabilities as assessed by the inverted cage lid, coat hanger and balance beam tests

increased startle reflex
- mice exhibit an exaggerated response to stimuli (110 db) starting at 38-44 days of age

craniofacial phenotype

abnormal olfactory epithelium morphology
- staining for a marker (olfactory marker protein) of mature olfactory cells is reduced in the olfactory epithelium
- the olfactory epithelium is disorganized and shows increased expression of galectin-3, especially near the basal membrane, indicating increased inflammatory processes

abnormal olfactory sensory neuron morphology
- architecture of olfactory receptor neurons is disturbed, showing enlarged gap-like spaces in the basal and middle portions of the epithelium

growth/size/body region phenotype

abnormal olfactory epithelium morphology
- staining for a marker (olfactory marker protein) of mature olfactory cells is reduced in the olfactory epithelium
- the olfactory epithelium is disorganized and shows increased expression of galectin-3, especially near the basal membrane, indicating increased inflammatory processes

abnormal olfactory sensory neuron morphology
- architecture of olfactory receptor neurons is disturbed, showing enlarged gap-like spaces in the basal and middle portions of the epithelium

decreased body weight
- adults, but not young mice, show reduced body weight

enlarged liver

enlarged spleen
- difference in weight from wild-type becomes significant at 40 days of age, but is no longer significant at 60 days probably due to wasting

weight loss
- significant weight loss observed at 6-7 weeks of age as compared to controls

hematopoietic system phenotype

enlarged spleen
- difference in weight from wild-type becomes significant at 40 days of age, but is no longer significant at 60 days probably due to wasting

microgliosis
- massive glia activation in the interface between axons of incoming olfactory receptor neurons and mitral cells/periglomerular cells in the olfactory bulb without neuronal loss in this area
- microgliosis is seen in the olfactory epithelium and olfactory bulb

homeostasis/metabolism phenotype

abnormal cellular cholesterol metabolism

abnormal lipid level
- GM2 levels are very high in the brain by 15 days of age and remain elevated
- GM3 levels begin to increase by 15 days of age and rise progressively until at least 90 days

decreased liver cholesterol level
- esterified cholesterol in liver tissue decreases with age

increased liver cholesterol level
- unesterified cholesterol in liver tissue increases with age

immune system phenotype

enlarged spleen
- difference in weight from wild-type becomes significant at 40 days of age, but is no longer significant at 60 days probably due to wasting

microgliosis
- massive glia activation in the interface between axons of incoming olfactory receptor neurons and mitral cells/periglomerular cells in the olfactory bulb without neuronal loss in this area
- microgliosis is seen in the olfactory epithelium and olfactory bulb

nasal inflammation
- macrophages are seen in the basal epithelial layer of the olfactory epithelium, crossing the basal membrane
- the olfactory epithelium and olfactory bulb show increased expression of galectin-3, indicating increased inflammatory processes

liver/biliary system phenotype

decreased liver cholesterol level
- esterified cholesterol in liver tissue decreases with age

enlarged liver

increased liver cholesterol level
- unesterified cholesterol in liver tissue increases with age

mammalian phenotype

nervous system phenotype
- Normal - unlike human Niemann-Pick Type C, neurofibrillary tangles are not found in the brain

mortality/aging

lethality, incomplete penetrance
- heterozygote matings produce less than the expected ratio of homozygotes (16-18% vs. 25%)

premature death
- average lifespan is 74 +/- 1.7 days

nervous system phenotype

abnormal cerebral cortex morphology
- accumulation of intracellular free cholesterol results in swollen neurons scattered throughout all neocortical layers; by 3 weeks of age, when clinical symptoms have not presented, there is accumulation of filipin staining in almost all neurons of the central cortex areas, cholesterol storage continues to increase, and by 10 weeks of age neuronal degeneration is found in the retrospinal cortex
- tral cortex areas, cholesterol storage continues to increase, and by 10 weeks of age neuronal degeneration is found in the retrospinal cortex

abnormal hippocampus CA3 region morphology
- 10 weeks of age
- although CA1 does not have intracellular free cholesterol accumulation, by 3 weeks of age there is filipin staining material in almost every pyramidal neuron in CA3 and this increases at 5 and 10 weeks of age with extensive degeneration of CA3 neurons by 10 weeks of age

abnormal neocortex morphology

abnormal olfactory bulb morphology
- the olfactory bulb shows increased expression of galectin-3, particularly in the glomerular cell layer, indicating increased inflammatory processes

abnormal olfactory nerve morphology
- the continuity of the olfactory nerve layer is disturbed
- the olfactory nerve layer shows a disrupted organization of staining for a maker of mature olfactory cells (olfactory marker protein)

abnormal olfactory sensory neuron morphology
- architecture of olfactory receptor neurons is disturbed, showing enlarged gap-like spaces in the basal and middle portions of the epithelium

abnormal pons morphology
- free cholesterol storage in neurons is found throughout the gigantocellular nucleus of the pons, but there is reduced cholesterol staining in the myelin sheaths of surrounding myelinated nerve fibers

abnormal trigeminal ganglion morphology
- myelin-like deposits in trigeminal ganglion cells and satellite cells

astrocytosis
- astrocytosis in the olfactory bulb, particularly within the glomerular layer

decreased brain weight
- decrease in brain weight of old mice

decreased prepulse inhibition
- prepulse inhibition is blunted (45-55%) when compared to wild-type (60-65%)

demyelination
- demyelination is observed in the corpus callosum, external capsule and internal capsule

microgliosis
- massive glia activation in the interface between axons of incoming olfactory receptor neurons and mitral cells/periglomerular cells in the olfactory bulb without neuronal loss in this area
- microgliosis is seen in the olfactory epithelium and olfactory bulb

neurodegeneration
- peripheral and central neurodgeneration in the olfactory system

Purkinje cell degeneration
- nearly all of the Purkinje cells are lost by 9 to 10 weeks of age
- pronounced loss of cerebellar Purkinje cells beginning at 6 weeks of age

cellular phenotype

abnormal cellular cholesterol metabolism

abnormal lysosome physiology
- marker analysis indicates an increase in lysosomal activity and lipid efflux

abnormal mitochondrial crista morphology

abnormal mitochondrial matrix morphology

abnormal mitochondrial physiology
- neurons and astrocytes from homozygous male cerebral cortices have decreased membrane potential relative to heterozygotes or wild-type controls and there are decreased ATP levels in brain, muscle, and liver at 9 weeks of age

abnormal mitochondrial shape

abnormal mitochondrion morphology
- cells of the cerebral cortex assessed from male homozygotes have smaller, more rounded mitochondria and translucent matrix and irregular cisternae

respiratory system phenotype

abnormal olfactory epithelium morphology
- staining for a marker (olfactory marker protein) of mature olfactory cells is reduced in the olfactory epithelium
- the olfactory epithelium is disorganized and shows increased expression of galectin-3, especially near the basal membrane, indicating increased inflammatory processes

abnormal olfactory sensory neuron morphology
- architecture of olfactory receptor neurons is disturbed, showing enlarged gap-like spaces in the basal and middle portions of the epithelium

nasal inflammation
- macrophages are seen in the basal epithelial layer of the olfactory epithelium, crossing the basal membrane
- the olfactory epithelium and olfactory bulb show increased expression of galectin-3, indicating increased inflammatory processes

taste/olfaction phenotype

abnormal olfactory epithelium morphology
- staining for a marker (olfactory marker protein) of mature olfactory cells is reduced in the olfactory epithelium
- the olfactory epithelium is disorganized and shows increased expression of galectin-3, especially near the basal membrane, indicating increased inflammatory processes

abnormal olfactory sensory neuron morphology
- architecture of olfactory receptor neurons is disturbed, showing enlarged gap-like spaces in the basal and middle portions of the epithelium

abnormal olfactory system morphology
- myelin-like lysosomal deposits in all types of cells of the peripheral and central olfactory system, including the supporting cells of the olfactory epithelium, the olfactory ensheathing cells of the lamina propria and central glia cells
- number of autophagosomes is high in ensheathing cells of nerve fiber layer of the olfactory bulb, in astrocytes and mitral cells and their dendrites

impaired olfaction
- olfaction is impaired as shown by decreased amplitudes in electro-olfactogram recordings after exposure of olfactory epithelium to different olfactory (phenyl ethyl alcohol and hydrogen sulfide) and trigeminal stimuli (carbon dioxide)

vision/eye phenotype

abnormal cornea morphology
- corneal basal cells do not have distinguishable borders and cytoplasm
- corneas exhibit an increase in dendritic cell number

corneal deposits
- corneas exhibit hyperreflective inclusions in intermediate and basal cells
- treatment with cyclodextrin/allopregnanolone results in regression of corneal inclusions

Genotype: Npc1^m1N/Npc1^m1N
involves: BALB/c * C57BL/6 * CBA

growth/size/body region phenotype

weight loss
- animals start to lose weight at weeks 5 to 6

hematopoietic system phenotype

abnormal microglial cell physiology
- cerebellar tissue samples display large accumulation of microglia with amoeboid morphology typical of activated cells whereas control tissue contains only resting microglia

homeostasis/metabolism phenotype

abnormal phospholipid level
- 80-day-old mice have increased levels of GM₂ and GM₃ gangliosides in the cerebral cortex compared to wild-type controls which exhibit no storage of gangliosides

immune system phenotype

abnormal microglial cell physiology
- cerebellar tissue samples display large accumulation of microglia with amoeboid morphology typical of activated cells whereas control tissue contains only resting microglia

mortality/aging

premature death
- animals die between 85-95 days of age

nervous system phenotype

abnormal microglial cell physiology
- cerebellar tissue samples display large accumulation of microglia with amoeboid morphology typical of activated cells whereas control tissue contains only resting microglia

Genotype: Npc1^m1N/Npc1^m1N
B6.C-Npc1

cellular phenotype

foam cell reticulosis
- mice exhibit proliferation of foamy cells in the liver unlike wild-type mice

immune system phenotype

microgliosis

liver/biliary system phenotype

increased liver cholesterol level
- Background Sensitivity - increased accumulation in P49 liver tissue as compared to BALB/c background

nervous system phenotype

astrocytosis

microgliosis

Purkinje cell degeneration
- at 7 weeks

hematopoietic system phenotype

microgliosis

homeostasis/metabolism phenotype

abnormal ceramide level
- Background Sensitivity - increased accumulation in P49 liver and brain tissue as compared to BALB/c background

abnormal lipid homeostasis

abnormal lipid level
- Background Sensitivity - increased lipid accumulation in P49 liver tissue as compared to BALB/c background
- Background Sensitivity - lipids include: ceramides, monohexosyceramides, sphingomyelins, sphingoid bases, gangiosides, free cholesterol, 24(S)-hydroxycholesterol, 4beta-hydroxy cholesterol and cholesterol ester

abnormal sphingomyelin level
- Background Sensitivity - increased accumulation in P49 liver tissue as compared to BALB/c background

increased cholesterol level
- mice exhibit an increase in unestrified cholesterol in the cerebellum compared with wild-type mice

increased liver cholesterol level
- Background Sensitivity - increased accumulation in P49 liver tissue as compared to BALB/c background

Genotype: Npc1^m1N/Npc1^m1N
BALB/c-Npc1

behavior/neurological phenotype

impaired coordination
- progressive decline in motor coordination after 4 weeks of age

cellular phenotype

abnormal primary cilium morphology
- analysis at postnatal day 12 finds slightly fewer ACIII stained hippocampal neurons, indicative of fewer neurons having a primary cilium, and immuno-electron microscopy shows that these cilia are also shorter than those of wild-type controls

increased macrophage derived foam cell number
- liver macrophages exhibit a progressive foamy transformation

immune system phenotype

abnormal macrophage morphology
- polymembranous storage bodies found in liver macrophages and hepatocytes

abnormal microglial cell activation
- progression and spatial pattern is more advanced in comparison to Npc1^tm1.1Dso homozygotes

increased macrophage derived foam cell number
- liver macrophages exhibit a progressive foamy transformation

increased microglial cell activation
- age dependent increase in microglial activity

liver/biliary system phenotype

abnormal hepatocyte morphology
- polymembranous storage bodies found in liver macrophages and hepatocytes

increased liver cholesterol level
- cholesterol accumulation in hepatocytes and liver macrophages

mortality/aging

premature death
- average lifespan of approximately 80 days
- mutants start to die at 73 days of age

nervous system phenotype

abnormal microglial cell activation
- progression and spatial pattern is more advanced in comparison to Npc1^tm1.1Dso homozygotes

abnormal Purkinje cell dendrite morphology

abnormal Purkinje cell morphology
- focal axonal swellings are found in Purkinje cells of the cerebellar and vestibular nuclei, the granular layer, and the white matter tracts, an accumulation of vesicular storage material in the cytoplasm of the somata is evident beginning between 4 and 8 weeks of age, dendritic arbors and thick megadendrites are also found and Purkinje cell axonal swellings are common in the granule layer
- polymembranous storage bodies are found in lobule X Purkinje cells from P63 mice

astrocytosis
- age dependent increase in astrocyte reactivity
- increase in astrocytosis and microglia activation
- progression and spatial pattern is more advanced in comparison to Npc1^tm1.1Dso homozygotes

decreased brain size

demyelination
- mutants exhibit demyelination in the white matter

increased brain cholesterol level
- cholesterol accumulation within cell bodies and axonal segments of neocortical neurons
- Background Sensitivity - decreased accumulation in P49 liver tissue as compared to C57BL/6 background, but level is higher than control
- mutants exhibit vesicular accumulation of cholesterol in the cerebellum
- subcellular storage of cholesterol in lobule X Purkinje neurons in P63 mice

increased microglial cell activation
- age dependent increase in microglial activity

Purkinje cell degeneration
- at 35 days of age Purkinje cell loss is not found, but by 45 days of age there is loss of zebrin II negative Purkinje cells throughout the cerebellum in a banded pattern which has bands of surviving Purkinje cells, but the posterior cerebellum only has some gaps in the molecular layer, especially in the hemispheres; at 60 days of age patterned Purkinje cell loss is clear in the posterior hemispheres and the anterior lobe of the cerebellum shows loss in bot the vermis and hemispheres, but the nodular zone and lobule X are resistant to this Purkinje cell loss.
- degree of loss is more severe at P63 than in Npc1^tm1.1Dso homozygotes
- lower number of surviving Purkinje cells in cerebellar lobes VIII and X
- progressive, age-dependent Purkinje cell degeneration

growth/size/body region phenotype

weight loss
- mutants exhibit a progressive weight loss from 4 weeks of age

hematopoietic system phenotype

abnormal macrophage morphology
- polymembranous storage bodies found in liver macrophages and hepatocytes

abnormal microglial cell activation
- progression and spatial pattern is more advanced in comparison to Npc1^tm1.1Dso homozygotes

increased macrophage derived foam cell number
- liver macrophages exhibit a progressive foamy transformation

increased microglial cell activation
- age dependent increase in microglial activity

homeostasis/metabolism phenotype

abnormal ceramide level
- Background Sensitivity - decreased accumulation in P49 liver tissue as compared to C57BL/6 background

abnormal ganglioside level
- GM2 and GM3 ganglioside accumulation is higher than in Npc1^tm1.1Dso homozygotes
- GM2 ganglioside accumulation within cell bodies and axonal segments of neocortical neurons
- subcellular storage of ganglioside GM2 in lobule X Purkinje neurons in P63 mice

abnormal lipid homeostasis

abnormal lipid level
- Background Sensitivity - decreased lipid accumulation in P49 liver tissue as compared to C57BL/6 background
- lipids include: ceramides, monohexosyceramides, sphingomyelins, sphingoid bases, gangiosides, free cholesterol, 24(S)-hydroxycholesterol, 4beta-hydroxy cholesterol and cholesterol ester

abnormal sphingomyelin level
- Background Sensitivity - decreased accumulation in P49 liver tissue as compared to C57BL/6 background

increased brain cholesterol level
- cholesterol accumulation within cell bodies and axonal segments of neocortical neurons
- Background Sensitivity - decreased accumulation in P49 liver tissue as compared to C57BL/6 background, but level is higher than control
- mutants exhibit vesicular accumulation of cholesterol in the cerebellum
- subcellular storage of cholesterol in lobule X Purkinje neurons in P63 mice

increased liver cholesterol level
- cholesterol accumulation in hepatocytes and liver macrophages

Genotype: Npc1^m1N/Npc1^m1N
involves: BALB/c * C3H/HeJ * C57BL/6J

behavior/neurological phenotype

abnormal object recognition memory
- mutants exhibit deficits in object memory index at 10 weeks of age, but not at 7 weeks of age, on the object recognition memory test
- mutants treated with 2-HPC at P7 to lower cholesterol accumulation show significant improvement in cognitive performance

hypoactivity
- mutants exhibit reduced locomotor activity and increased periods of inactivity in open-field tests at 10 weeks of age
- mutants treated with 2-HPC at P7 to lower cholesterol accumulation show significant improvement in motor performance

impaired coordination
- mutants exhibit impaired rotarod performance and gait coordination at 10 weeks of age but not at 4 or 7 weeks of age
- mutants treated with 2-HPC at P7 to lower cholesterol accumulation show significant improvement in motor performance

immune system phenotype

microgliosis
- mutants exhibit microglial activation in the hippocampus and cerebellum, however at a lower level than in double Npc1 and Tg(PRNP-APPSweInd)8Dwst mutants
- mutants treated with 2-HPC at P7 to lower cholesterol accumulation show lower microglia activation compared to saline-injected mutants

mortality/aging

premature death
- mutants exhibit a reduced lifespan with only 30% of mice living past 90 days
- mutants treated with 2-hydroxypropyl-beta-cyclodextrin (2-HPC) at P7 to lower cholesterol accumulation live significantly longer than saline-injected mutants, with a median survival of 107 days versus 85 days

nervous system phenotype

demyelination
- mutants exhibit demyelination in the hippocampus/cortex and cerebellum, however demyelination is less severe than in double Npc1 and Tg(PRNP-APPSweInd)8Dwst mutants at earlier stages

increased brain cholesterol level
- Normal - however total cholesterol content in the hippocampus and cerebellum is not altered compared with controls
- mutants exhibit intracellular accumulation of unesterified cholesterol in the hippocampus and cerebellum at 4, 7, and 10 weeks of age

microgliosis
- mutants exhibit microglial activation in the hippocampus and cerebellum, however at a lower level than in double Npc1 and Tg(PRNP-APPSweInd)8Dwst mutants
- mutants treated with 2-HPC at P7 to lower cholesterol accumulation show lower microglia activation compared to saline-injected mutants

neurodegeneration
- neurodgeneration in the cerebellum

Purkinje cell degeneration
- decrease in the number of cerebellar Purkinje cells; cell loss is less pronounced than in double Npc1 and Tg(PRNP-APPSweInd)8Dwst mutants
- Normal - however neuronal loss in the hippocampus is not seen
- mutants treated with 2-HPC at P7 to lower cholesterol accumulation show decreased Purkinje cell loss compared to saline-injected mutants

hematopoietic system phenotype

microgliosis
- mutants exhibit microglial activation in the hippocampus and cerebellum, however at a lower level than in double Npc1 and Tg(PRNP-APPSweInd)8Dwst mutants
- mutants treated with 2-HPC at P7 to lower cholesterol accumulation show lower microglia activation compared to saline-injected mutants

homeostasis/metabolism phenotype

abnormal enzyme/coenzyme level
- cathepsin D levels and activity are higher in the hippocampus and the cerebellum than in controls, although this is lower than in double Npc1 and Tg(PRNP-APPSweInd)8Dwst mutants
- cytosolic cathepsin D, cytochrome c and Bcl-2-associated X protein levels are increased in the cerebellum although to a lower level than in double Npc1 and Tg(PRNP-APPSweInd)8Dwst mutants

increased brain cholesterol level
- Normal - however total cholesterol content in the hippocampus and cerebellum is not altered compared with controls
- mutants exhibit intracellular accumulation of unesterified cholesterol in the hippocampus and cerebellum at 4, 7, and 10 weeks of age

References

Lopez ME; Klein AD; Dimbil UJ; Scott MP. 2011. Anatomically defined neuron-based rescue of neurodegenerative niemann-pick type C disorder. J Neurosci 31(12):4367-78PubMed: 21430138 MGI: J:170312

Additional - Npc1^m1N related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Separated PCR:Npc1
- Standard PCR:Npc1Alternate1
- Separated MCA:Npc1
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live FVB-congenic colony, heterozygous mice are bred with wildtype mice from the colony or with FVB/NJ inbred mice (Stock No. 001800).
Heterozygotes are viable and fertile. Homozygotes demonstrate progressive motor coordination deficits and survive a mean of 76 days. Heterozygous FVB background animals may breed earlier and for longer periods of time than the original BALB/cNctr background mice (see Stock No. 003092).
- Additional Breeding and Husbandry Support
Citation
When using the FVB.C-Npc1^m1N/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #021755 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous or wildtype for Npc1<m1N>

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Donating Investigator

Genetic overview

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Detailed Description

Development

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Additional Information

Selected References

Npc1m1N

Allele Symbol: Npc1m1N

Disease Terms

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Npc1m1N related

Mammalian Phenotype Terms by Genotype

Genotype: Npc1m1N/Npc1m1Ninvolves: BALB/c

adipose tissue phenotype

reproductive system phenotype

endocrine/exocrine gland phenotype

respiratory system phenotype

behavior/neurological phenotype

growth/size/body region phenotype

hematopoietic system phenotype

cardiovascular system phenotype

homeostasis/metabolism phenotype

cellular phenotype

immune system phenotype

liver/biliary system phenotype

mortality/aging

nervous system phenotype

Genotype: Npc1m1N/Npc1m1Ninvolves: 129S1/Sv * BALB/c * C57BL/6

growth/size/body region phenotype

liver/biliary system phenotype

mortality/aging

nervous system phenotype

homeostasis/metabolism phenotype

Genotype: Npc1m1N/Npc1m1Ninvolves: 129S2/SvPas * BALB/c * C57BL/6

mortality/aging

Genotype: Npc1m1N/Npc1m1NBALB/cNctr-Npc1/J

behavior/neurological phenotype

craniofacial phenotype

growth/size/body region phenotype

hematopoietic system phenotype

homeostasis/metabolism phenotype

immune system phenotype

liver/biliary system phenotype

mammalian phenotype

mortality/aging

nervous system phenotype

cellular phenotype

respiratory system phenotype

taste/olfaction phenotype

vision/eye phenotype

Genotype: Npc1m1N/Npc1m1Ninvolves: BALB/c * C57BL/6 * CBA

growth/size/body region phenotype

hematopoietic system phenotype

homeostasis/metabolism phenotype

immune system phenotype

mortality/aging

nervous system phenotype

Genotype: Npc1m1N/Npc1m1NB6.C-Npc1

cellular phenotype

immune system phenotype

liver/biliary system phenotype

nervous system phenotype

hematopoietic system phenotype

homeostasis/metabolism phenotype

Genotype: Npc1m1N/Npc1m1NBALB/c-Npc1

behavior/neurological phenotype

cellular phenotype

immune system phenotype

liver/biliary system phenotype

mortality/aging

nervous system phenotype

growth/size/body region phenotype

hematopoietic system phenotype

homeostasis/metabolism phenotype

Genotype: Npc1m1N/Npc1m1Ninvolves: BALB/c * C3H/HeJ * C57BL/6J

Npc1^m1N

Allele Symbol: Npc1^m1N

Genotype: Npc1^m1N related

Genotype: Npc1^m1N/Npc1^m1N
involves: BALB/c

Genotype: Npc1^m1N/Npc1^m1N
involves: 129S1/Sv * BALB/c * C57BL/6

Genotype: Npc1^m1N/Npc1^m1N
involves: 129S2/SvPas * BALB/c * C57BL/6

Genotype: Npc1^m1N/Npc1^m1N
BALB/cNctr-Npc1/J

Genotype: Npc1^m1N/Npc1^m1N
involves: BALB/c * C57BL/6 * CBA

Genotype: Npc1^m1N/Npc1^m1N
B6.C-Npc1

Genotype: Npc1^m1N/Npc1^m1N
BALB/c-Npc1

Genotype: Npc1^m1N/Npc1^m1N
involves: BALB/c * C3H/HeJ * C57BL/6J

Additional - Npc1^m1N related