Mouse Genome Informatics
hm1
    Npc1m1N/Npc1m1N
B6.C-Npc1m1N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system

hematopoietic system

homeostasis/metabolism
• mice exhibit an increase in unestrified cholesterol in the cerebellum compared with wild-type mice

cellular
• mice exhibit proliferation of foamy cells in the liver unlike wild-type mice

immune system

Mouse Models of Human Disease
OMIM IDRef(s)
Niemann-Pick Disease, Type C1; NPC1 257220 J:157113


Mouse Genome Informatics
hm2
    Npc1m1N/Npc1m1N
BALB/c-Npc1m1N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mutants start to die at 73 days of age

growth/size
• mutants exhibit a progressive weight loss from 4 weeks of age

nervous system
• mutants exhibit vesicular accumulation of cholesterol in the cerebellum
• lower number of surviving Purkinje cells in cerebellar lobes VIII and X
• increase in astrocytosis and microglia activation
• mutants exhibit demyelination in the white matter

behavior/neurological
• progressive decline in motor coordination after 4 weeks of age

homeostasis/metabolism
• mutants exhibit vesicular accumulation of cholesterol in the cerebellum

Mouse Models of Human Disease
OMIM IDRef(s)
Niemann-Pick Disease, Type C1; NPC1 257220 J:172769


Mouse Genome Informatics
hm3
    Npc1m1N/Npc1m1N
BALB/cNctr-Npc1m1N/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
N
• unlike human Niemann-Pick Type C, neurofibrillary tangles are not found in the brain (J:149812)
• 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
• 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
• 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
• nearly all of the Purkinje cells are lost by 9 to 10 weeks of age (J:149812)
• pronounced loss of cerebellar Purkinje cells beginning at 6 weeks of age (J:179744)
• demyelination is observed in the corpus callosum, external capsule and internal capsule
• prepulse inhibition is blunted (45-55%) when compared to wild-type (60-65%)

cellular

homeostasis/metabolism
• 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
• esterified cholesterol in liver tissue decreases with age
• unesterified cholesterol in liver tissue increases with age

behavior/neurological
• mice exhibit an exaggerated response to stimuli (110 db) starting at 38-44 days of age
• first observed as a lateral displacement of each rear foot at 7 weeks of age
• decrease in motor capabilities as assessed by the inverted cage lid, coat hanger and balance beam tests
• first observed at 9 weeks of age

growth/size
• significant weight loss observed at 6-7 weeks of age as compared to controls

hematopoietic system
• 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

immune system
• 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

liver/biliary system
• esterified cholesterol in liver tissue decreases with age
• unesterified cholesterol in liver tissue increases with age

mortality/aging
• heterozygote matings produce less than the expected ratio of homozygotes (16-18% vs. 25%)
• average lifespan is 74 +/- 1.7 days

vision/eye
• corneal basal cells do not have distinguishable borders and cytoplasm
• corneas exhibit an increase in dendritic cell number
• corneas exhibit hyperreflective inclusions in intermediate and basal cells
• treatment with cyclodextrin/allopregnanolone results in regression of corneal inclusions

Mouse Models of Human Disease
OMIM IDRef(s)
Niemann-Pick Disease, Type C1; NPC1 257220 J:182268


Mouse Genome Informatics
hm4
    Npc1m1N/Npc1m1N
involves: 129S1/Sv * BALB/c * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Neurodegenerative changes affecting cerebullar Purkinje cells of Npc1m1N/Npc1m1N, Npc2tm1Plob/Npc2tm1Plob, and double homozygous mice for Npc1m1N and Npc2tm1Plob

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

growth/size
• earlier onset and faster progression than in Npc2tm1Plob homozygotes

homeostasis/metabolism
• 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
• 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

liver/biliary system
• 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
OMIM IDRef(s)
Niemann-Pick Disease, Type C1; NPC1 257220 J:89617


Mouse Genome Informatics
hm5
    Npc1m1N/Npc1m1N
involves: 129S2/SvPas * BALB/c * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• lifespan of Npc1-null mice expressing Il6 is modestly reduced compared to double null littermates


Mouse Genome Informatics
hm6
    Npc1m1N/Npc1m1N
involves: BALB/c
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Abnormal morphology of Npc1m1N/Npc1m1N sperm

mortality/aging
• ~75 day life span (J:81305)
• mice die between 80 and 100 days of age from neurodegenerative disease (J:130969)

behavior/neurological
• poor food intake, beginning at 7 weeks of age
• defects beginning at 7 to 8 weeks of age
• mice exhibit impaired coordination around 40 days of age with coordination worsening as the mice age

growth/size
• female homozygotes display a smaller stature than wild-type females
• female homozygotes display a reduced body mass relative to wild-type females (J:91430)
• beginning at 7 to 8 weeks of age (J:76733)
• mice exhibit weight loss starting at 40 days of age (J:130969)

hematopoietic system
• 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
• progressive splenomegaly, beginning at 7 weeks of age

homeostasis/metabolism
• higher rate of turnover although whole body pool is considerably elevated
• rate of cholesterol synthesis is reduced
• female homozygotes show a 25% increase in serum FSH levels relative to wild-type controls
• female homozygotes show a dramatic increase in serum LH levels relative to wild-type controls
• in contrast, pituitary expression and circulating levels of GH remain unaffected
• mutant pituitaries exhibit decreased concentrations of prolactin, consistent with a significant reduction in pituitary prolactin mRNA
• 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
• female homozygotes show a dramatic reduction in serum prolactin levels relative to wild-type controls
• elevation in lipid content in the lungs
• decreased levels in the brain at 7 weeks of age relative to controls (J:104996)
• mice have decreased levels of total cholesterol in the brain (J:130969)
• elevated in most organs except the brain at 7 weeks of age (J:104996)
• elevated in the brain at 1 day of age (J:104996)
• mice have increased cholesterol levels in the liver, spleen, intestine and lung (J:130969)
• increase in cholesterol content in the lungs (J:204311)
• 12-fold elevation of cholesterol levels in branchoalveolar lavage (J:204311)
• 6.8-fold increase in cholesterol levels in lamellar bodies (J:204311)
• progressively increasing plasma cholesterol levels
• increase in phospholipid content in the lungs
• 4-fold elevation of phospholipid levels of bronchoalveolar lavage
• 2- to 2.8-fold increase in phospholipid levels in lamellar bodies
• increase in surfactant phospholipid levels
• lipid accumulation (including sphingomyelin, glucocerebroside, lactosylceramide, and cholesterol) in various organs including the liver, lung, kidney, thymus, spleen, and brain (J:18511)
• at 7-8 weeks of age, female homozygotes show lipid accumulation in mural granulosa cells and in the ovarian stroma, as shown by oil-red-O staining (J:91430)
• lungs exhibit surfactant accumulation, indicating alveolar lipidosis (J:204311)
• proteinaceous-like material in the alveolar space
• mild protein accumulation in bronchoalveolar lavage

immune system
• 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
• progressive splenomegaly, beginning at 7 weeks of age

liver/biliary system
• hepatomegaly and associated pale liver, presumably due to lipid accumulation
• progressive increase in liver weight, beginning at 7 weeks of age
• massive liver storage of cholesterol in mice on a high fat, 1% cholesterol diet

reproductive system
• some mutant seminiferous tubules exhibit evidence of extensive degeneration (J:119302)
• adult mutant ovaries show near absence of 17beta-estradiol (E2) content (2.0 pg) relative to 110-135 pg/ovary in wild-type controls (J:91430)
• expression of two key steroidogenic proteins (StAR and Cyp19) is markedly reduced in mutant ovaries relative to wild-type controls (J:91430)
• however, exogenous gonadotropin treatment restores expression of both steroidogenic proteins to wild-type levels (J:91430)
• at 7-8 weeks of age, female homozygotes exhibit a thinner reproductive tract than wild-type females (J:91430)
• at 7-8 weeks of age, the stromata of mutant ovaries contain numerous islands of foamy cells composed of healthy nuclei and vacuolated cytoplasm (J:91430)
• these cell nests are replete with lipid, as shown by oil-red-O staining (J:91430)
• at 7-8 weeks of age, no formation of corpora lutea is observed (J:91430)
• 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 (J:91430)
• at 7 weeks of age, mutant ovarian follicles and stromata exhibit lipid accumulation, as shown by oil-red-O staining (J:91430)
• at 7-8 weeks of age, mutant mural granulosa cells exhibit lipid accumulation, as shown by oil-red-O staining (J:91430)
• mutant ovarian follicles fail to mature to the large antral and preovulatory stages (J:91430)
• at 7 weeks of age, mutant antral follicles are smaller than the largest follicles found in wild-type controls (J:91430)
• the number of mutant secondary and antral follicles is reduced relative to wild-type controls (J:91430)
• 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 (J:91430)
• 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 (J:91430)
• at 7-8 weeks, but not at 3 weeks, of age mutant ovaries are smaller than wild-type (J:91430)
• 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 (J:91430)
• at 7-8 weeks of age, reduction in the endometrial stroma is associated with a reduction in the convolution of uterine glands (J:91430)
• at 8 weeks of age, a reduction in endometrial thickness is observed (J:91430)
(J:91430)
• at 7-8 weeks of age, mutant uteri are thinner than wild-type (J:91430)
• at 7-8 weeks of age, atrophy of the myometrium, endometrial stroma, and the endometrial epithelium is observed (J:91430)
• at 60 days of age, the total number of mutant cauda sperm is reduced to only ~28% of that in wild-type males (J:119302)
• 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) (J:119302)
• at 60 days of age, tailless sperm heads are frequently observed (J:119302)
• at 60 days of age, aberrant cauda sperm heads are frequentyly observed (J:119302)
• at 60 days of age, headless sperm tails are frequently observed (J:119302)
• 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 (J:119302)
• at 7-8 weeks of age, mutant ovaries display no evidence of ovulation (J:91430)
• 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 (J:91430)
• mutant ovaries transplanted under wild-type kidney capsules display evidence of ovulation, as shown by the presence of corpora lutea and an extraovarian oocyte (J:91430)
• female homozygotes are acyclic (J:91430)
• females showed normal oogenesis, but lacked implantation sites after successful plugging
• female homozygotes are infertile (J:91430)
• male homozygotes are infertile (J:119302)
• in vitro, 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 (J:119302)
• 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 (J:119302)
• interestingly, 30% of total cyritestin protein is not proteolytically processed on mutant cauda sperm, whereas fertilin beta is processed normally (J:119302)
• 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

respiratory system
• lungs contain 'nests' of vacuolar filled macrophages and enlarged foamy alveolar macrophages
• 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
• 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
• proteinaceous-like material in the alveolar space
• mild protein accumulation in bronchoalveolar lavage
• alveolar type II cells have many autophagosomes
• cholesterol and phospholipid accumulation in lamellar bodies of alveolar type II cells
• 42% of alveolar type II cell lamellar bodies are enlarged compared to 15% in wild-type mice
• progressive increase in lung weight, beginning at 7 weeks of age (J:76733)
• lung weight as a % of total body weight is higher (J:204311)
• thickening of the intra-alveolar septae with a slight enlargement of the airways
• liposome degradation is reduced by 46% in the lungs
• increase in surfactant phospholipid levels

nervous system
• the mutant anterior pituitary displays vacuolated cells, suggestiing low rates of feedback control and increased hormone synthesis and secretion
• the mutant anterior pituitary shows a dramatic reduction in acidophil cell number relative to wild-type
• however, chronic (4-week) treatment with 17beta-estradiol (E2) restores pituitary volume and acidophil numbers to wild-type levels
• the mutant anterior pituitary is hypoplastic relative to wild-type
• decreased levels in the brain at 7 weeks of age relative to controls (J:104996)
• mice have decreased levels of total cholesterol in the brain (J:130969)
• progressive decrease in brain weight, beginning at 7 weeks of age (J:76733)
• brain weight is lower than in controls mice (J:130969)
• reduced in size by 50% at 11 weeks of age
• glial cells reduced by 52%
• by P45, Purkinje cell loss was most evident in the anterior cerebellar vermis
• degenerating cells belonged preferentially to the zebrin II-negative subtype
• by P45, some Purkinje cell loss was evident in the posterior cerebellar vermis
• at P60, most surviving Purkinje cells were located in the posterior vermis
• cerebellum weight is smaller than controls
• glial cells in the corpus callosum reduced by 52%
• vacuolated cytoplasmic storage material in all regions of the central nervous system
• axonal swelling by 11 weeks of age
• localized axonal swellings, malformations of the dendritic arbor, and accumulation of vesicular storage materials within the cytoplasm
• 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 (J:81305)
• small reduction in Purkinje cell numbers in the cerebellar hemispheres at 3 weeks of age (J:126474)
• reduction in numbers increases with age (J:126474)
• reduced levels of both myelin protein and myelin cholesterol

cellular
• at 60 days of age, tailless sperm heads are frequently observed (J:119302)
• higher rate of turnover although whole body pool is considerably elevated
• rate of cholesterol synthesis is reduced

adipose tissue
• female homozygotes exhibit reduced abdominal fat deposits relative to wild-type females

endocrine/exocrine glands
• the mutant anterior pituitary displays vacuolated cells, suggestiing low rates of feedback control and increased hormone synthesis and secretion
• the mutant anterior pituitary shows a dramatic reduction in acidophil cell number relative to wild-type
• however, chronic (4-week) treatment with 17beta-estradiol (E2) restores pituitary volume and acidophil numbers to wild-type levels
• the mutant anterior pituitary is hypoplastic relative to wild-type
• at 7-8 weeks of age, the stromata of mutant ovaries contain numerous islands of foamy cells composed of healthy nuclei and vacuolated cytoplasm (J:91430)
• these cell nests are replete with lipid, as shown by oil-red-O staining (J:91430)
• at 7-8 weeks of age, no formation of corpora lutea is observed (J:91430)
• 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 (J:91430)
• at 7 weeks of age, mutant ovarian follicles and stromata exhibit lipid accumulation, as shown by oil-red-O staining (J:91430)
• at 7-8 weeks of age, mutant mural granulosa cells exhibit lipid accumulation, as shown by oil-red-O staining (J:91430)
• mutant ovarian follicles fail to mature to the large antral and preovulatory stages (J:91430)
• at 7 weeks of age, mutant antral follicles are smaller than the largest follicles found in wild-type controls (J:91430)
• the number of mutant secondary and antral follicles is reduced relative to wild-type controls (J:91430)
• 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 (J:91430)
• 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 (J:91430)
• at 7-8 weeks, but not at 3 weeks, of age mutant ovaries are smaller than wild-type (J:91430)
• 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 (J:91430)
• some mutant seminiferous tubules exhibit evidence of extensive degeneration (J:119302)
• adult mutant ovaries show near absence of 17beta-estradiol (E2) content (2.0 pg) relative to 110-135 pg/ovary in wild-type controls (J:91430)
• expression of two key steroidogenic proteins (StAR and Cyp19) is markedly reduced in mutant ovaries relative to wild-type controls (J:91430)
• however, exogenous gonadotropin treatment restores expression of both steroidogenic proteins to wild-type levels (J:91430)

cardiovascular system
• 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

Mouse Models of Human Disease
OMIM IDRef(s)
Niemann-Pick Disease, Type C1; NPC1 257220 J:18511 , J:76733 , J:81305 , J:130969 , J:204311


Mouse Genome Informatics
hm7
    Npc1m1N/Npc1m1N
involves: BALB/c * C3H/HeJ * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• 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

behavior/neurological
• 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
• 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
• 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

nervous system
• 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
• mutants exhibit intracellular accumulation of unesterified cholesterol in the hippocampus and cerebellum at 4, 7, and 10 weeks of age
• however total cholesterol content in the hippocampus and cerebellum is not altered compared with controls
• neurodgeneration in the cerebellum
• decrease in the number of cerebellar Purkinje cells; cell loss is less pronounced than in double Npc1 and Tg(PRNP-APPSweInd)8Dwst mutants
• 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
• 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

hematopoietic system
• 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
• 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
• mutants exhibit intracellular accumulation of unesterified cholesterol in the hippocampus and cerebellum at 4, 7, and 10 weeks of age
• however total cholesterol content in the hippocampus and cerebellum is not altered compared with controls

immune system
• 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

Mouse Models of Human Disease
OMIM IDRef(s)
Niemann-Pick Disease, Type C1; NPC1 257220 J:188345


Mouse Genome Informatics
hm8
    Npc1m1N/Npc1m1N
involves: BALB/c * C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• animals die between 85-95 days of age

growth/size
• animals start to lose weight at weeks 5 to 6

nervous system
• cerebellar tissue samples display large accumulation of microglia with amoeboid morphology typical of activated cells whereas control tissue contains only resting microglia

homeostasis/metabolism
• 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
• cerebellar tissue samples display large accumulation of microglia with amoeboid morphology typical of activated cells whereas control tissue contains only resting microglia

hematopoietic system
• cerebellar tissue samples display large accumulation of microglia with amoeboid morphology typical of activated cells whereas control tissue contains only resting microglia


Mouse Genome Informatics
ht9
    Npc1m1N/Npc1tm1.2Apl
B6.Cg-Npc1m1N/Npc1tm1.2Apl
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice die around 49 days of age
• no mice survive longer than 9 weeks

nervous system

behavior/neurological
• on a rotarod

growth/size
• at weaning
• at 7 weeks of age

homeostasis/metabolism
• mice exhibit an increase in unestrified cholesterol in the cerebellum compared with wild-type mice

cellular
• mice exhibit proliferation of foamy cells in the liver unlike wild-type mice

immune system

hematopoietic system

Mouse Models of Human Disease
OMIM IDRef(s)
Niemann-Pick Disease, Type C1; NPC1 257220 J:157113


Mouse Genome Informatics
cx10
    Apptm1Dbo/Apptm1Dbo
Npc1m1N/Npc1m1N

C.Cg-Apptm1Dbo Npc1m1N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mutants start to die at 50 days of age

growth/size
• mutants exhibit severe weight loss, with weight at 3 weeks of age lower than seen in single homozygous App mice, but then increases so that by 12 weeks of age, loss of body weight is similar to single Npc1 homozygotes

nervous system
• mutants exhibit a greater vesicular accumulation of and wider distribution of cholesterol in the cerebellum, the motor cortex, the hippocampus and dentate gyrus than single Npc1 homozygotes
• lower number of surviving Purkinje cells in cerebellar lobes VIII and X
• mutants exhibit a greater increase in astrocytosis and microglia activation than in single Npc1 homozygotes
• mutants exhibit demyelination in the white matter

behavior/neurological
• mutants exhibit an exacerbated motor coordination deficit than seen in single Npc1 homozygotes

homeostasis/metabolism
• mutants exhibit a greater vesicular accumulation of and wider distribution of cholesterol in the cerebellum, the motor cortex, the hippocampus and dentate gyrus than single Npc1 homozygotes


Mouse Genome Informatics
cx11
    Abcb1atm1Bor/Abcb1atm1Bor
Npc1m1N/Npc1m1N

involves: 129/Ola * BALB/c
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• neurological symptoms apparent and progressive, beginning at ~ day 50 of life
• failed to care for pups (J:76395)

homeostasis/metabolism
• cholesterol accumulation in liver

reproductive system
N
• mice were fertile (J:76395)

liver/biliary system
• cholesterol accumulation in liver

Mouse Models of Human Disease
OMIM IDRef(s)
Niemann-Pick Disease, Type C1; NPC1 257220 J:76395


Mouse Genome Informatics
cx12
    Npc1m1N/Npc1m1N
Tlr4tm1Aki/Tlr4tm1Aki

involves: 129P2/OlaHsd * BALB/c
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• fibroblasts isolated from 6-week old double null mice secrete ~30% of levels in Tlr-4-sufficient, Npc1-null fibroblasts

nervous system
N
• number of activated glial cells in brains of double mutants is not different from Npc1-null brains (J:118352)


Mouse Genome Informatics
cx13
    Apoetm1Unc/Apoetm1Unc
Npc1m1N/Npc1m1N

involves: 129P2/OlaHsd * BALB/c
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism


Mouse Genome Informatics
cx14
    Abca1tm1Wpfl/Abca1tm1Wpfl
Npc1m1N/Npc1m1N

involves: 129P2/OlaHsd * BALB/c
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice die between 80 and 100 days of age from neurodegenerative disease

homeostasis/metabolism
• mice have decreased levels of total cholesterol in the brain
• mice have increased cholesterol levels in the liver, spleen, intestine and lung though not to extent observed in Npc1 mutants on a wild-type background

nervous system
• mice have decreased levels of total cholesterol in the brain


Mouse Genome Informatics
cx15
    Npc1m1N/Npc1m1N
Npc2tm1Plob/Npc2tm1Plob

involves: 129S1/Sv * BALB/c * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Neurodegenerative changes affecting cerebullar Purkinje cells of Npc1m1N/Npc1m1N, Npc2tm1Plob/Npc2tm1Plob, and double homozygous mice for Npc1m1N and Npc2tm1Plob

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

growth/size

homeostasis/metabolism
• 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
• 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
• similar progressive degeneration of loss as in Npc1m1 homozygotes

liver/biliary system
• 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
OMIM IDRef(s)
Niemann-Pick Disease, Type C1; NPC1 257220 J:89617


Mouse Genome Informatics
cx16
    Il6tm1Kopf/Il6tm1Kopf
Npc1m1N/Npc1m1N

involves: 129S2/SvPas * BALB/c * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• nmber of activated microglial and astroglial cells is decreased in 6-week old mice compared to Il6-sufficient, Npc1-null mice


Mouse Genome Informatics
cx17
    Npc1m1N/Npc1m1N
Nr1h2tm1Djm/Nr1h2tm1Djm

involves: 129S6/SvEvTac * BALB/c
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice die between 60 and 90 days of age from neurodegenerative disease, which is significantly faster than Npc1 mutants on a wild-type background

Mouse Models of Human Disease
OMIM IDRef(s)
Niemann-Pick Disease, Type C1; NPC1 257220 J:130969


Mouse Genome Informatics
cx18
    Ldlrtm1Her/Ldlrtm1Her
Npc1m1N/Npc1m1N

involves: 129S7/SvEvBrd * BALB/c
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice die between 80 and 100 days of age from neurodegenerative disease

nervous system
• mice have decreased levels of total cholesterol in the brain
• reduced in size by 50% at 11 weeks of age
• glial cells reduced by 44%
• axonal swelling by 11 weeks of age
• small reduction in Purkinje cell numbers in the cerebellar hemispheres at 3 weeks of age
• reduction in numbers increases with age
• glial cells in the corpus callosum reduced by 44%

homeostasis/metabolism
• mice have decreased levels of total cholesterol in the brain
• mice have increased cholesterol levels in the liver, spleen, intestine and lung to a greater extant than that observed in Npc1 mutants on a wild-type background
• plasma LDL levels are increased 15-fold in these mice (J:130969)


Mouse Genome Informatics
cx19
    Ldlrtm1Her/Ldlrtm1Her
Npc1m1N/Npc1m1N

involves: 129S7/SvEvBrd * BALB/c * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• some early death among males on a high fat 1% cholesterol diet

liver/biliary system
• in mice on a high fat, 1% cholesterol diet
• increased liver weight to 14% of body weight in mice that die early
• liver reaches 22% of body weight in mice that live longer


Mouse Genome Informatics
cx20
    Npc1m1N/Npc1m1N
Tg(PRNP-APPSweInd)8Dwst/0

involves: BALB/c * C3H/HeJ * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mutants have a maximum lifespan of 77 days, with mortality rate increasing drastically from 55 days onward
• 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 103 days versus 69 days

growth/size
• mutants reach a maximum body weight of approximately 12 grams by 6 weeks of age which is about 30% less compared to controls
• weight declines progressively after 6 weeks of age until death

behavior/neurological
• mutants exhibit deficits in object memory index at 7 and 10 weeks of age; object recognition memory deficits are accelerated compared to single Npc1 homozygotes
• mutants treated with 2-HPC at P7 to lower cholesterol accumulation show significant improvement in cognitive performance
• mutants exhibit impaired rotarod performance and gait coordination at 7 weeks of age which is further exacerbated by 10 weeks of age
• mutants treated with 2-HPC at P7 to lower cholesterol accumulation show significant improvement in motor performance
• mutants exhibit reduced locomotor activity and increased periods of inactivity in open-field tests at both 7 and 10 weeks of age
• mutants treated with 2-HPC at P7 to lower cholesterol accumulation show significant improvement in motor performance

nervous system
• mutants exhibit microglial activation in the hippocampus and cerebellum at a higher level than in single Npc1 homozygotes
• mutants treated with 2-HPC at P7 to lower cholesterol accumulation show lower microglia activation compared to saline-injected mutants
• mutants exhibit intracellular accumulation of unesterified cholesterol in the hippocampus and cerebellum at 4, 7, and 10 weeks of age
• however total cholesterol content in the hippocampus and cerebellum is not altered compared with controls
• mutants exhibit a profound increase in the number and activation of glial fibrillary acidic protein (GFAP)-labeled astrocytes in the hippocampus and cerebellum compared with wild-type, single Tg(PRNP-APPSweInd)8Dwst mutants, and single Npc1 homozygotes
• mutants treated with 2-HPC at P7 to lower cholesterol accumulation show decreased astrocyte activation compared to saline-injected mutants
• neurodgeneration in the cerebellum is accelerated compared to single Npc1 homozygotes
• decrease in the number of cerebellar Purkinje cells that is more pronounced than in single Npc1 homozygotes
• however neuronal loss in the hippocampus is not seen
• mutants exhibit a loss of myelin fibre tracts in the hippocampus/cortex and cerebellum, indicating significant demyelination; demyelination is more severe than in single Npc1 homozygotes

hematopoietic system
• mutants exhibit microglial activation in the hippocampus and cerebellum at a higher level than in single Npc1 homozygotes
• mutants treated with 2-HPC at P7 to lower cholesterol accumulation show lower microglia activation compared to saline-injected mutants

homeostasis/metabolism
• cathepsin D levels are higher in the hippocampus and the cerebellum than in controls, including single Npc1 homozygotes
• cytosolic cathepsin D, cytochrome c and Bcl-2-associated X protein levels are increased in the cerebellum to a higher level than in single Npc1 homozygotes
• mutants exhibit intracellular accumulation of unesterified cholesterol in the hippocampus and cerebellum at 4, 7, and 10 weeks of age
• however total cholesterol content in the hippocampus and cerebellum is not altered compared with controls
• cathepsin D activity is higher in the hippocampus and the cerebellum than in controls, including single Npc1 homozygotes

immune system
• mutants exhibit microglial activation in the hippocampus and cerebellum at a higher level than in single Npc1 homozygotes
• mutants treated with 2-HPC at P7 to lower cholesterol accumulation show lower microglia activation compared to saline-injected mutants


Mouse Genome Informatics
cx21
    Npc1m1N/Npc1m1N
Tg(CAG-RAB9A)500Repa/0

involves: BALB/c * C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• male mice have a 22% increase in lifespan compared to transgene-negative Npc1 homozygotes which die around 95 days of age

growth/size
• animals lose weight more slowly than transgene positive Npc1 homozygotes; at all time points after the 4 weeks, weight differences are significantly different
• transgene-positive animals show a trend to increased weight retention; retardation in weight loss is more pronounced for males relative to females

homeostasis/metabolism
• 80-day-old mice have reduced levels of GM2 and GM3 gangliosides (by 45 and 32%) in the cerebral cortex compared to transgene-negative Npc1 homozygotes