Phenotypes associated with this allele

• Allele Symbol: Npc1^m1N
• Allele Name: Niemann Pick type C1 NIH
• Allele ID: MGI:1857409
• Summary: 24 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Npc1^m1N/Npc1^m1N	B6.C-Npc1^m1N	MGI:4436745
hm2	Npc1^m1N/Npc1^m1N	BALB/cNctr-Npc1^m1N/J	MGI:3849202
hm3	Npc1^m1N/Npc1^m1N	BALB/c-Npc1^m1N	MGI:5305070
hm4	Npc1^m1N/Npc1^m1N	involves: 129S1/Sv * BALB/c * C57BL/6	MGI:3044831
hm5	Npc1^m1N/Npc1^m1N	involves: 129S2/SvPas * BALB/c * C57BL/6	MGI:3706956
hm6	Npc1^m1N/Npc1^m1N	involves: BALB/c	MGI:2386738
hm7	Npc1^m1N/Npc1^m1N	involves: BALB/c * C3H/HeJ * C57BL/6J	MGI:5442413
hm8	Npc1^m1N/Npc1^m1N	involves: BALB/c * C57BL/6 * CBA	MGI:3849459
ht9	Npc1^m1N/Npc1^tm1.2Apl	B6.Cg-Npc1^m1N/Npc1^tm1.2Apl	MGI:4436744
cn10	Npc1^m1N/Npc1^tm1.1Apl Tg(CAG-cre/Esr1*)5Amc/0	B6J.Cg-Npc1^m1N/Npc1^tm1.1Apl Tg(CAG-cre/Esr1*)5Amc	MGI:5925342
cn11	Npc1^m1N/Npc1^tm1.1Apl Tg(GFAP-cre/ERT2)13Kdmc/0	B6J.Cg-Npc1^m1N/Npc1^tm1.1Apl Tg(GFAP-cre/ERT2)13Kdmc	MGI:5925344
cn12	Npc1^m1N/Npc1^tm1.1Apl Tg(Syn1-cre)671Jxm/0	B6J.Cg-Npc1^m1N/Npc1^tm1.1Apl Tg(Syn1-cre)671Jxm	MGI:5925346
cx13	App^tm1Dbo/App^tm1Dbo Npc1^m1N/Npc1^m1N	C.Cg-App^tm1Dbo Npc1^m1N	MGI:5305067
cx14	Abcb1a^tm1Bor/Abcb1a^tm1Bor Npc1^m1N/Npc1^m1N	involves: 129/Ola * BALB/c	MGI:2386740
cx15	Apoe^tm1Unc/Apoe^tm1Unc Npc1^m1N/Npc1^m1N	involves: 129P2/OlaHsd * BALB/c	MGI:3785902
cx16	Npc1^m1N/Npc1^m1N Tlr4^tm1Aki/Tlr4^tm1Aki	involves: 129P2/OlaHsd * BALB/c	MGI:3706954
cx17	Abca1^tm1Wpfl/Abca1^tm1Wpfl Npc1^m1N/Npc1^m1N	involves: 129P2/OlaHsd * BALB/c	MGI:4359170
cx18	Npc1^m1N/Npc1^m1N Npc2^tm1Plob/Npc2^tm1Plob	involves: 129S1/Sv * BALB/c * C57BL/6	MGI:3044885
cx19	Il6^tm1Kopf/Il6^tm1Kopf Npc1^m1N/Npc1^m1N	involves: 129S2/SvPas * BALB/c * C57BL/6	MGI:3706955
cx20	Npc1^m1N/Npc1^m1N Nr1h2^tm1Djm/Nr1h2^tm1Djm	involves: 129S6/SvEvTac * BALB/c	MGI:4359169
cx21	Ldlr^tm1Her/Ldlr^tm1Her Npc1^m1N/Npc1^m1N	involves: 129S7/SvEvBrd * BALB/c	MGI:3785901
cx22	Ldlr^tm1Her/Ldlr^tm1Her Npc1^m1N/Npc1^m1N	involves: 129S7/SvEvBrd * BALB/c * C57BL/6	MGI:4367225
cx23	Npc1^m1N/Npc1^m1N Tg(PRNP-APPSweInd)8Dwst/0	involves: BALB/c * C3H/HeJ * C57BL/6J	MGI:5442379
cx24	Npc1^m1N/Npc1^m1N Tg(CAG-RAB9A)500Repa/0	involves: BALB/c * C57BL/6 * CBA	MGI:3849460

Genotype
MGI:4436745

hm1

• Allelic Composition: Npc1^m1N/Npc1^m1N
• Genetic Background: B6.C-Npc1^m1N

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

nervous system

microgliosis ( J:157113 )

Purkinje cell degeneration ( J:157113 )

• at 7 weeks

astrocytosis ( J:157113 )

hematopoietic system

microgliosis ( J:157113 )

homeostasis/metabolism

abnormal lipid homeostasis ( J:221855 )

abnormal lipid level ( J:221855 )

• 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

increased cholesterol level ( J:157113 )

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

increased liver cholesterol level ( J:221855 )

• Background Sensitivity: increased accumulation in P49 liver tissue as compared to BALB/c background

abnormal sphingomyelin level ( J:221855 )

• Background Sensitivity: increased accumulation in P49 liver tissue as compared to BALB/c background

abnormal ceramide level ( J:221855 )

• Background Sensitivity: increased accumulation in P49 liver and brain tissue as compared to BALB/c background

cellular

foam cell reticulosis ( J:157113 )

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

immune system

microgliosis ( J:157113 )

liver/biliary system

increased liver cholesterol level ( J:221855 )

• Background Sensitivity: increased accumulation in P49 liver tissue as compared to BALB/c background

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Niemann-Pick disease		DOID:14504		J:157113

Genotype
MGI:3849202

hm2

• Allelic Composition: Npc1^m1N/Npc1^m1N
• Genetic Background: BALB/cNctr-Npc1^m1N/J

nervous system

nervous system phenotype ( J:149812 )

N • unlike human Niemann-Pick Type C, neurofibrillary tangles are not found in the brain

abnormal olfactory sensory neuron morphology ( J:209834 )

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

microgliosis ( J:209834 )

• microgliosis is seen in the olfactory epithelium and olfactory bulb

• 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

decreased brain weight ( J:209834 )

• decrease in brain weight of old mice

abnormal pons morphology ( 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

abnormal hippocampus CA3 region morphology ( J:149812 )

• 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 cerebral cortex morphology ( J:149812 )

• 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

abnormal neocortex morphology ( J:149812 )

abnormal olfactory bulb morphology ( J:209834 )

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

astrocytosis ( J:209834 )

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

abnormal trigeminal ganglion morphology ( J:209834 )

• myelin-like deposits in trigeminal ganglion cells and satellite cells

abnormal olfactory nerve morphology ( J:209834 )

• 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)

neurodegeneration ( J:209834 )

• peripheral and central neurodgeneration in the olfactory system

Purkinje cell degeneration ( J:149812 , J:179744 )

• 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 ( J:179744 )

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

decreased prepulse inhibition ( J:179744 )

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

cellular

abnormal mitochondrial morphology ( J:98011 )

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

abnormal mitochondrial crista morphology ( J:98011 )

abnormal mitochondrial matrix morphology ( J:98011 )

abnormal mitochondrial shape ( J:98011 )

abnormal cellular cholesterol metabolism ( J:149812 )

abnormal lysosome physiology ( J:209834 )

• marker analysis indicates an increase in lysosomal activity and lipid efflux

abnormal mitochondrial physiology ( J:98011 )

• 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

homeostasis/metabolism

abnormal cellular cholesterol metabolism ( J:149812 )

abnormal lipid level ( J:179744 )

• 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 ( J:179744 )

• esterified cholesterol in liver tissue decreases with age

increased liver cholesterol level ( J:179744 )

• unesterified cholesterol in liver tissue increases with age

behavior/neurological

increased startle reflex ( J:179744 )

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

ataxia ( J:179744 )

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

impaired coordination ( J:179744 )

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

decreased grip strength ( J:179744 )

• first observed at 9 weeks of age

growth/size/body

abnormal olfactory epithelium morphology ( J:209834 )

• the olfactory epithelium is disorganized and shows increased expression of galectin-3, especially near the basal membrane, indicating increased inflammatory processes

• staining for a marker (olfactory marker protein) of mature olfactory cells is reduced in the olfactory epithelium

abnormal olfactory sensory neuron morphology ( J:209834 )

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

decreased body weight ( J:209834 )

• adults, but not young mice, show reduced body weight

weight loss ( J:179744 )

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

enlarged liver ( J:179744 )

enlarged spleen ( J:179744 )

• 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

hematopoietic system

enlarged spleen ( J:179744 )

• 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 ( J:209834 )

• microgliosis is seen in the olfactory epithelium and olfactory bulb

• 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

immune system

enlarged spleen ( J:179744 )

• 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 ( J:209834 )

• microgliosis is seen in the olfactory epithelium and olfactory bulb

• 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

nasal inflammation ( J:209834 )

• the olfactory epithelium and olfactory bulb show increased expression of galectin-3, indicating increased inflammatory processes

• macrophages are seen in the basal epithelial layer of the olfactory epithelium, crossing the basal membrane

liver/biliary system

enlarged liver ( J:179744 )

decreased liver cholesterol level ( J:179744 )

• esterified cholesterol in liver tissue decreases with age

increased liver cholesterol level ( J:179744 )

• unesterified cholesterol in liver tissue increases with age

mortality/aging

lethality, incomplete penetrance ( J:179744 )

• heterozygote matings produce less than the expected ratio of homozygotes (16-18% vs. 25%)

premature death ( J:179744 )

• average lifespan is 74 +/- 1.7 days

vision/eye

abnormal cornea morphology ( J:182268 )

• corneal basal cells do not have distinguishable borders and cytoplasm

• corneas exhibit an increase in dendritic cell number

corneal deposits ( J:182268 )

• corneas exhibit hyperreflective inclusions in intermediate and basal cells

• treatment with cyclodextrin/allopregnanolone results in regression of corneal inclusions

craniofacial

abnormal olfactory epithelium morphology ( J:209834 )

• the olfactory epithelium is disorganized and shows increased expression of galectin-3, especially near the basal membrane, indicating increased inflammatory processes

• staining for a marker (olfactory marker protein) of mature olfactory cells is reduced in the olfactory epithelium

abnormal olfactory sensory neuron morphology ( J:209834 )

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

respiratory system

abnormal olfactory epithelium morphology ( J:209834 )

• the olfactory epithelium is disorganized and shows increased expression of galectin-3, especially near the basal membrane, indicating increased inflammatory processes

• staining for a marker (olfactory marker protein) of mature olfactory cells is reduced in the olfactory epithelium

abnormal olfactory sensory neuron morphology ( J:209834 )

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

nasal inflammation ( J:209834 )

• the olfactory epithelium and olfactory bulb show increased expression of galectin-3, indicating increased inflammatory processes

• macrophages are seen in the basal epithelial layer of the olfactory epithelium, crossing the basal membrane

taste/olfaction

abnormal olfactory system morphology ( J:209834 )

• 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

abnormal olfactory epithelium morphology ( J:209834 )

• the olfactory epithelium is disorganized and shows increased expression of galectin-3, especially near the basal membrane, indicating increased inflammatory processes

• staining for a marker (olfactory marker protein) of mature olfactory cells is reduced in the olfactory epithelium

abnormal olfactory sensory neuron morphology ( J:209834 )

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

impaired olfaction ( J:209834 )

• 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)

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Niemann-Pick disease		DOID:14504		J:182268 , J:209834

Genotype
MGI:5305070

hm3

• Allelic Composition: Npc1^m1N/Npc1^m1N
• Genetic Background: BALB/c-Npc1^m1N

mortality/aging

premature death ( J:172769 , J:221855 )

• mutants start to die at 73 days of age (J:172769)

• average lifespan of approximately 80 days (J:221855)

growth/size/body

weight loss ( J:172769 )

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

nervous system

abnormal microglial cell activation ( J:221855 )

• progression and spatial pattern is more advanced in comparison to Npc1^tm1.1Dso homozygotes

increased microglial cell activation ( J:221855 )

• age dependent increase in microglial activity

increased brain cholesterol level ( J:172769 , J:221855 )

• mutants exhibit vesicular accumulation of cholesterol in the cerebellum (J:172769)

• subcellular storage of cholesterol in lobule X Purkinje neurons in P63 mice (J:221855)

• cholesterol accumulation within cell bodies and axonal segments of neocortical neurons (J:221855)

• Background Sensitivity: decreased accumulation in P49 liver tissue as compared to C57BL/6 background, but level is higher than control (J:221855)

decreased brain size ( J:172769 )

abnormal Purkinje cell morphology ( J:221855 )

• polymembranous storage bodies are found in lobule X Purkinje cells from P63 mice

Purkinje cell degeneration ( J:81305 , J:172769 , J:221855 )

• 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. (J:81305)

• lower number of surviving Purkinje cells in cerebellar lobes VIII and X (J:172769)

• progressive, age-dependent Purkinje cell degeneration (J:221855)

• degree of loss is more severe at P63 than in Npc1^tm1.1Dso homozygotes (J:221855)

abnormal Purkinje cell focal axonal swelling ( J:81305 )

• 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

abnormal Purkinje cell dendrite morphology ( J:81305 )

astrocytosis ( J:172769 , J:221855 )

• increase in astrocytosis and microglia activation (J:172769)

• age dependent increase in astrocyte reactivity (J:221855)

• progression and spatial pattern is more advanced in comparison to Npc1^tm1.1Dso homozygotes (J:221855)

demyelination ( J:172769 )

• mutants exhibit demyelination in the white matter

behavior/neurological

impaired coordination ( J:172769 )

• progressive decline in motor coordination after 4 weeks of age

homeostasis/metabolism

abnormal lipid homeostasis ( J:221855 )

abnormal lipid level ( J:221855 )

• 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

increased brain cholesterol level ( J:172769 , J:221855 )

• mutants exhibit vesicular accumulation of cholesterol in the cerebellum (J:172769)

• subcellular storage of cholesterol in lobule X Purkinje neurons in P63 mice (J:221855)

• cholesterol accumulation within cell bodies and axonal segments of neocortical neurons (J:221855)

• Background Sensitivity: decreased accumulation in P49 liver tissue as compared to C57BL/6 background, but level is higher than control (J:221855)

increased liver cholesterol level ( J:221855 )

• cholesterol accumulation in hepatocytes and liver macrophages

abnormal sphingomyelin level ( J:221855 )

• Background Sensitivity: decreased accumulation in P49 liver tissue as compared to C57BL/6 background

abnormal ceramide level ( J:221855 )

• Background Sensitivity: decreased accumulation in P49 liver tissue as compared to C57BL/6 background

abnormal ganglioside level ( J:221855 )

• GM2 ganglioside accumulation within cell bodies and axonal segments of neocortical neurons

• GM2 and GM3 ganglioside accumulation is higher than in Npc1^tm1.1Dso homozygotes

• subcellular storage of ganglioside GM2 in lobule X Purkinje neurons in P63 mice

cellular

abnormal primary cilium morphology ( J:242832 )

• 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 ( J:221855 )

• liver macrophages exhibit a progressive foamy transformation

hematopoietic system

abnormal macrophage morphology ( J:221855 )

• polymembranous storage bodies found in liver macrophages and hepatocytes

increased macrophage derived foam cell number ( J:221855 )

• liver macrophages exhibit a progressive foamy transformation

abnormal microglial cell activation ( J:221855 )

• progression and spatial pattern is more advanced in comparison to Npc1^tm1.1Dso homozygotes

increased microglial cell activation ( J:221855 )

• age dependent increase in microglial activity

immune system

abnormal macrophage morphology ( J:221855 )

• polymembranous storage bodies found in liver macrophages and hepatocytes

increased macrophage derived foam cell number ( J:221855 )

• liver macrophages exhibit a progressive foamy transformation

abnormal microglial cell activation ( J:221855 )

• progression and spatial pattern is more advanced in comparison to Npc1^tm1.1Dso homozygotes

increased microglial cell activation ( J:221855 )

• age dependent increase in microglial activity

liver/biliary system

increased liver cholesterol level ( J:221855 )

• cholesterol accumulation in hepatocytes and liver macrophages

abnormal hepatocyte morphology ( J:221855 )

• polymembranous storage bodies found in liver macrophages and hepatocytes

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Niemann-Pick disease		DOID:14504		J:172769

Genotype
MGI:3044831

hm4

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

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

mortality/aging

premature death ( J:89617 )

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

growth/size/body

weight loss ( J:89617 )

• earlier onset and faster progression than in Npc2^tm1Plob homozygotes

homeostasis/metabolism

abnormal lipid homeostasis ( J:89617 )

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

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

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

increased liver cholesterol level ( J:89617 )

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

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

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

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

nervous system

Purkinje cell degeneration ( J:89617 )

liver/biliary system

increased liver cholesterol level ( J:89617 )

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

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

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

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

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

Genotype
MGI:3706956

hm5

• Allelic Composition: Npc1^m1N/Npc1^m1N
• Genetic Background: involves: 129S2/SvPas * BALB/c * C57BL/6

mortality/aging

premature death ( J:118352 )

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

Genotype
MGI:2386738

hm6

• Allelic Composition: Npc1^m1N/Npc1^m1N
• Genetic Background: involves: BALB/c

Abnormal morphology of Npc1^m1N/Npc1^m1N sperm

mortality/aging

premature death ( J:81305 , J:130969 )

• ~75 day life span (J:81305)

• mice die between 80 and 100 days of age from neurodegenerative disease (J:130969)

behavior/neurological

decreased food intake ( J:76733 )

• poor food intake, beginning at 7 weeks of age

abnormal motor capabilities/coordination/movement ( J:76733 )

• defects beginning at 7 to 8 weeks of age

impaired coordination ( J:130969 )

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

growth/size/body

decreased body size ( J:91430 )

• female homozygotes display a smaller stature than wild-type females

decreased body weight ( J:91430 , J:204311 )

• female homozygotes display a reduced body mass relative to wild-type females (J:91430)

weight loss ( J:76733 , J:130969 )

• beginning at 7 to 8 weeks of age (J:76733)

• mice exhibit weight loss starting at 40 days of age (J:130969)

increased lung weight ( J:76733 , J:204311 )

• 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)

enlarged liver ( J:91430 )

• hepatomegaly and associated pale liver, presumably due to lipid accumulation

increased liver weight ( J:76733 )

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

enlarged spleen ( J:76733 )

• progressive splenomegaly, beginning at 7 weeks of age

hematopoietic system

enlarged spleen ( J:76733 )

• progressive splenomegaly, beginning at 7 weeks of age

abnormal alveolar macrophage morphology ( J:204311 )

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

• alveolar macrophages are laden with free cholesterol with many large, foamy cells; phospholipid levels are elevated 6-fold and cholesterol levels are elevated 15-fold in alveolar macrophages

homeostasis/metabolism

abnormal cellular cholesterol metabolism ( J:104996 )

• higher rate of turnover although whole body pool is considerably elevated

• rate of cholesterol synthesis is reduced

increased circulating follicle stimulating hormone level ( J:91430 )

• female homozygotes show a 25% increase in serum FSH levels relative to wild-type controls

increased circulating luteinizing hormone level ( J:91430 )

• 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

decreased prolactin level ( J:91430 )

• 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

decreased circulating prolactin level ( J:91430 )

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

abnormal lipid level ( J:204311 )

• elevation in lipid content in the lungs

decreased brain cholesterol level ( J:104996 , J:130969 )

• 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)

increased cholesterol level ( J:104996 , J:130969 , J:204311 )

• 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)

increased circulating cholesterol level ( J:18511 )

• progressively increasing plasma cholesterol levels

abnormal phospholipid level ( J:204311 )

• 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

lipidosis ( J:18511 , J:204311 )

• lipid accumulation (including sphingomyelin, glucocerebroside, lactosylceramide, and cholesterol) in various organs including the liver, lung, kidney, thymus, spleen, and brain (J:18511)

• lungs exhibit surfactant accumulation, indicating alveolar lipidosis (J:204311)

pulmonary alveolar proteinosis ( J:204311 )

• proteinaceous-like material in the alveolar space

• mild protein accumulation in bronchoalveolar lavage

immune system

enlarged spleen ( J:76733 )

• progressive splenomegaly, beginning at 7 weeks of age

abnormal alveolar macrophage morphology ( J:204311 )

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

• alveolar macrophages are laden with free cholesterol with many large, foamy cells; phospholipid levels are elevated 6-fold and cholesterol levels are elevated 15-fold in alveolar macrophages

liver/biliary system

enlarged liver ( J:91430 )

• hepatomegaly and associated pale liver, presumably due to lipid accumulation

increased liver weight ( J:76733 )

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

hepatic steatosis ( J:100351 )

• massive liver storage of cholesterol in mice on a high fat, 1% cholesterol diet

pale liver ( J:91430 )

reproductive system

oligozoospermia ( J:119302 )

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

teratozoospermia ( 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)

absent sperm flagellum ( J:119302 )

♂ • at 60 days of age, tailless sperm heads are frequently observed

abnormal sperm head morphology ( J:119302 )

♂ • at 60 days of age, aberrant cauda sperm heads are frequentyly observed

absent sperm head ( J:119302 )

♂ • at 60 days of age, headless sperm tails are frequently observed

seminiferous tubule degeneration ( J:119302 )

♂ • some mutant seminiferous tubules exhibit evidence of extensive degeneration

decreased ovary secretion ( J:91430 )

♀ • 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

♀ • however, exogenous gonadotropin treatment restores expression of both steroidogenic proteins to wild-type levels

abnormal female reproductive system morphology ( J:91430 )

♀ • at 7-8 weeks of age, female homozygotes exhibit a thinner reproductive tract than wild-type females

decreased endometrial gland number ( J:91430 )

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

abnormal ovary morphology ( 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

♀ • these cell nests are replete with lipid, as shown by oil-red-O staining

absent corpus luteum ( J:91430 )

♀ • 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

abnormal ovarian follicle morphology ( J:91430 )

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

abnormal granulosa cell morphology ( J:91430 )

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

absent mature ovarian follicles ( J:91430 )

♀ • mutant ovarian follicles fail to mature to the large antral and preovulatory stages

decreased secondary ovarian follicle number ( J:91430 )

♀ • number of mutant secondary follicles is reduced relative to wild-type controls

♀ • chronic treatment of 8-wk-old female mutants with 17beta-estradiol (E2) increases the number of secondary follicles, well in excess of that found in untreated mutant ovaries

abnormal tertiary ovarian follicle morphology ( J:91430 )

♀ • at 7 weeks of age, mutant antral follicles are smaller than the largest follicles found in wild-type controls

♀ • 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

decreased tertiary ovarian follicle number ( J:91430 )

♀ • number of mutant antral follicles is reduced relative to wild-type controls

♀ • chronic treatment of 8-wk-old female mutants with 17beta-estradiol (E2) increases the number of large antral follicles, well in excess of that found in untreated mutant ovaries

small ovary ( J:91430 )

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

decreased ovary weight ( 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

endometrium atrophy ( J:91430 )

♀

thin endometrium ( J:91430 )

♀ • at 8 weeks of age, a reduction in endometrial thickness is observed

thin myometrium ( J:91430 )

♀

thin uterus ( J:91430 )

♀ • at 7-8 weeks of age, mutant uteri are thinner than wild-type

uterus atrophy ( J:91430 )

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

arrest of spermatogenesis ( 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

decreased superovulation rate ( 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

anovulation ( J:91430 )

♀ • at 7-8 weeks of age, mutant ovaries display no evidence of ovulation

♀ • mutant ovaries transplanted under wild-type kidney capsules display evidence of ovulation, as shown by the presence of corpora lutea and an extraovarian oocyte

absent estrous cycle ( J:91430 )

♀ • female homozygotes are acyclic

infertility ( J:76395 )

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

female infertility ( J:91430 )

♀ • female homozygotes are infertile

male infertility ( J:119302 )

♂ • male homozygotes are infertile

impaired fertilization ( 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

• 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

impaired binding of sperm to zona pellucida ( 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

abnormal sperm physiology ( J:119302 )

♂ • 30% of total cyritestin protein is not proteolytically processed on mutant cauda sperm, whereas fertilin beta is processed normally

respiratory system

abnormal lung morphology ( J:204311 )

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

abnormal lung vasculature morphology ( J:204311 )

• 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

increased lung weight ( J:76733 , J:204311 )

• 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)

abnormal alveolar macrophage morphology ( J:204311 )

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

• alveolar macrophages are laden with free cholesterol with many large, foamy cells; phospholipid levels are elevated 6-fold and cholesterol levels are elevated 15-fold in alveolar macrophages

pulmonary alveolar proteinosis ( J:204311 )

• proteinaceous-like material in the alveolar space

• mild protein accumulation in bronchoalveolar lavage

abnormal type II pneumocyte morphology ( J:204311 )

• alveolar type II cells have many autophagosomes

abnormal alveolar lamellar body morphology ( J:204311 )

• cholesterol and phospholipid accumulation in lamellar bodies of alveolar type II cells

enlarged alveolar lamellar bodies ( J:204311 )

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

thick pulmonary interalveolar septum ( J:204311 )

• thickening of the intra-alveolar septae with a slight enlargement of the airways

abnormal respiratory system physiology ( J:204311 )

• liposome degradation is reduced by 46% in the lungs

abnormal surfactant composition ( J:204311 )

• increase in surfactant phospholipid levels

nervous system

abnormal adenohypophysis morphology ( J:91430 )

• the mutant anterior pituitary displays vacuolated cells, suggestiing low rates of feedback control and increased hormone synthesis and secretion

decreased lactotroph cell number ( J:91430 )

• 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

adenohypophysis hypoplasia ( J:91430 )

• the mutant anterior pituitary is hypoplastic relative to wild-type

decreased brain cholesterol level ( J:104996 , J:130969 )

• 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)

decreased brain weight ( J:76733 , 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)

decreased corpus callosum size ( J:126474 )

• reduced in size by 50% at 11 weeks of age

• glial cells reduced by 52%

abnormal cerebellum anterior vermis morphology ( J:81305 )

• 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 ( J:81305 )

• 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

small cerebellum ( J:130969 )

• cerebellum weight is smaller than controls

abnormal CNS glial cell morphology ( J:126474 )

• glial cells in the corpus callosum reduced by 52%

abnormal neuron morphology ( J:104996 )

• vacuolated cytoplasmic storage material in all regions of the central nervous system

Purkinje cell degeneration ( J:81305 )

• localized axonal swellings, malformations of the dendritic arbor, and accumulation of vesicular storage materials within the cytoplasm

abnormal Purkinje cell axon morphology ( J:126474 )

• axonal swelling by 11 weeks of age

decreased Purkinje cell number ( J:81305 , J:126474 )

• 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)

abnormal myelination ( J:104996 )

• reduced levels of both myelin protein and myelin cholesterol

cellular

oligozoospermia ( J:119302 )

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

teratozoospermia ( 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)

absent sperm flagellum ( J:119302 )

♂ • at 60 days of age, tailless sperm heads are frequently observed

abnormal sperm head morphology ( J:119302 )

♂ • at 60 days of age, aberrant cauda sperm heads are frequentyly observed

absent sperm head ( J:119302 )

♂ • at 60 days of age, headless sperm tails are frequently observed

abnormal Golgi apparatus morphology ( J:267948 )

• Golgi fragmentation is found in neurons of the cerebral cortex, cerebellar Purkinje cells, and brainstem neurons

abnormal cellular cholesterol metabolism ( J:104996 )

• higher rate of turnover although whole body pool is considerably elevated

• rate of cholesterol synthesis is reduced

adipose tissue

decreased abdominal fat pad weight ( J:91430 )

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

endocrine/exocrine glands

abnormal adenohypophysis morphology ( J:91430 )

• the mutant anterior pituitary displays vacuolated cells, suggestiing low rates of feedback control and increased hormone synthesis and secretion

decreased lactotroph cell number ( J:91430 )

• 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

adenohypophysis hypoplasia ( J:91430 )

• the mutant anterior pituitary is hypoplastic relative to wild-type

decreased endometrial gland number ( J:91430 )

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

abnormal ovary morphology ( 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

♀ • these cell nests are replete with lipid, as shown by oil-red-O staining

absent corpus luteum ( J:91430 )

♀ • 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

abnormal ovarian follicle morphology ( J:91430 )

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

abnormal granulosa cell morphology ( J:91430 )

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

absent mature ovarian follicles ( J:91430 )

♀ • mutant ovarian follicles fail to mature to the large antral and preovulatory stages

decreased secondary ovarian follicle number ( J:91430 )

♀ • number of mutant secondary follicles is reduced relative to wild-type controls

♀ • chronic treatment of 8-wk-old female mutants with 17beta-estradiol (E2) increases the number of secondary follicles, well in excess of that found in untreated mutant ovaries

abnormal tertiary ovarian follicle morphology ( J:91430 )

♀ • at 7 weeks of age, mutant antral follicles are smaller than the largest follicles found in wild-type controls

♀ • 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

decreased tertiary ovarian follicle number ( J:91430 )

♀ • number of mutant antral follicles is reduced relative to wild-type controls

♀ • chronic treatment of 8-wk-old female mutants with 17beta-estradiol (E2) increases the number of large antral follicles, well in excess of that found in untreated mutant ovaries

small ovary ( J:91430 )

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

decreased ovary weight ( 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

seminiferous tubule degeneration ( J:119302 )

♂ • some mutant seminiferous tubules exhibit evidence of extensive degeneration

decreased ovary secretion ( J:91430 )

♀ • 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

♀ • however, exogenous gonadotropin treatment restores expression of both steroidogenic proteins to wild-type levels

cardiovascular system

abnormal lung vasculature morphology ( J:204311 )

• 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		DO ID	OMIM ID(s)	Ref(s)
Niemann-Pick disease		DOID:14504		J:18511 , J:76733 , J:81305 , J:130969 , J:204311

Genotype
MGI:5442413

hm7

• Allelic Composition: Npc1^m1N/Npc1^m1N
• Genetic Background: involves: BALB/c * C3H/HeJ * C57BL/6J

mortality/aging

premature death ( J:188345 )

• 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

abnormal object recognition memory ( J:188345 )

• 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

impaired coordination ( J:188345 )

• 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

decreased locomotor activity ( J:188345 )

• 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

microgliosis ( J:188345 )

• 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

increased brain cholesterol level ( J:188345 )

• 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

neurodegeneration ( J:188345 )

• neurodgeneration in the cerebellum

Purkinje cell degeneration ( J:188345 )

• 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

demyelination ( J:188345 )

• 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

microgliosis ( J:188345 )

• 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

abnormal enzyme/coenzyme level ( J:188345 )

• 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 ( J:188345 )

• 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

microgliosis ( J:188345 )

• 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		DO ID	OMIM ID(s)	Ref(s)
Niemann-Pick disease		DOID:14504		J:188345

Genotype
MGI:3849459

hm8

• Allelic Composition: Npc1^m1N/Npc1^m1N
• Genetic Background: involves: BALB/c * C57BL/6 * CBA

mortality/aging

premature death ( J:144240 )

• animals die between 85-95 days of age

growth/size/body

weight loss ( J:144240 )

• animals start to lose weight at weeks 5 to 6

nervous system

abnormal microglial cell physiology ( J:144240 )

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

homeostasis/metabolism

abnormal phospholipid level ( J:144240 )

• 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

abnormal microglial cell physiology ( J:144240 )

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

hematopoietic system

abnormal microglial cell physiology ( J:144240 )

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

Genotype
MGI:4436744

ht9

• Allelic Composition: Npc1^m1N/Npc1^tm1.2Apl
• Genetic Background: B6.Cg-Npc1^m1N/Npc1^tm1.2Apl

mortality/aging

premature death ( J:157113 )

• mice die around 49 days of age

• no mice survive longer than 9 weeks

nervous system

microgliosis ( J:157113 )

Purkinje cell degeneration ( J:157113 )

• at 7 weeks

astrocytosis ( J:157113 )

behavior/neurological

impaired coordination ( J:157113 )

• on a rotarod

growth/size/body

decreased body size ( J:157113 )

• at weaning

weight loss ( J:157113 )

• at 7 weeks of age

homeostasis/metabolism

increased cholesterol level ( J:157113 )

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

cellular

foam cell reticulosis ( J:157113 )

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

immune system

microgliosis ( J:157113 )

hematopoietic system

microgliosis ( J:157113 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Niemann-Pick disease		DOID:14504		J:157113

Genotype
MGI:5925342

cn10

• Allelic Composition: Npc1^m1N/Npc1^tm1.1Apl; Tg(CAG-cre/Esr1*)5Amc/0
• Genetic Background: B6J.Cg-Npc1^m1N/Npc1^tm1.1Apl Tg(CAG-cre/Esr1*)5Amc

mortality/aging

premature death ( J:176888 )

• average lifespan is 109 days post tamoxifen injection

nervous system

microgliosis ( J:176888 )

• widespread microgliosis in the cerebellum of tamoxifen-treated mice at 18 weeks of age

increased brain cholesterol level ( J:176888 )

• accumulation of unesterified cholesterol in cerebellar lobule X in tamoxifen-treated mice at 18 weeks of age

Purkinje cell degeneration ( J:176888 )

• progressive anterior-to-posterior Purkinje cell loss in tamoxifen-treated mice

• cells in anterior lobules degenerate early and those in posterior lobules are more resistant to degeneration

astrocytosis ( J:176888 )

• widespread astrocytosis in the cerebellum of tamoxifen-treated mice at 18 weeks of age

abnormal axon morphology ( J:176888 )

• tamoxifen-treated mice exhibit swollen axons in the cortex at 22 weeks of age

axonal spheroids ( J:176888 )

• widespread axonal spheroids in the cerebellum of tamoxifen-treated mice at 18 weeks of age

demyelination ( J:176888 )

• tamoxifen-treated mice exhibit demyelination in the corpus callosum at 22 weeks of age

• widespread secondary demyelination in the cerebellum of tamoxifen-treated mice at 18 weeks of age

behavior/neurological

impaired balance ( J:176888 )

• mice injected with tamoxifen at 6 weeks of age exhibit impaired balance beam performance by 12 weeks which progresses with age

growth/size/body

weight loss ( J:176888 )

• mice injected with tamoxifen at 6 weeks of age start to lose weight around 16 weeks of age

hematopoietic system

microgliosis ( J:176888 )

• widespread microgliosis in the cerebellum of tamoxifen-treated mice at 18 weeks of age

homeostasis/metabolism

increased brain cholesterol level ( J:176888 )

• accumulation of unesterified cholesterol in cerebellar lobule X in tamoxifen-treated mice at 18 weeks of age

immune system

microgliosis ( J:176888 )

• widespread microgliosis in the cerebellum of tamoxifen-treated mice at 18 weeks of age

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Niemann-Pick disease		DOID:14504		J:176888

Genotype
MGI:5925344

cn11

• Allelic Composition: Npc1^m1N/Npc1^tm1.1Apl; Tg(GFAP-cre/ERT2)13Kdmc/0
• Genetic Background: B6J.Cg-Npc1^m1N/Npc1^tm1.1Apl Tg(GFAP-cre/ERT2)13Kdmc

normal phenotype

no abnormal phenotype detected ( J:176888 )

• mice treated with tamoxifen at 6 weeks of age exhibit normal weight gain, motor performance, and survival and do not show Purkinje cell loss, axonal spheroids, demyelination, or activated astrocytes or microglia in the cerebellum, and no functional alterations in synaptic transmission

Genotype
MGI:5925346

cn12

• Allelic Composition: Npc1^m1N/Npc1^tm1.1Apl; Tg(Syn1-cre)671Jxm/0
• Genetic Background: B6J.Cg-Npc1^m1N/Npc1^tm1.1Apl Tg(Syn1-cre)671Jxm

mortality/aging

premature death ( J:176888 )

• mice show early death, with an average lifespan of 105 days

nervous system

microgliosis ( J:176888 )

• mice show activated microglia in many brain regions

increased brain cholesterol level ( J:176888 )

astrocytosis ( J:176888 )

• mice show activated astrocytes in many brain regions

abnormal axon morphology ( J:176888 )

• mice show severe axonal pathology

axonal spheroids ( J:176888 )

• mice exhibit frequent axonal spheroids in the brainstem

demyelination ( J:176888 )

• mice show loss of myelinated fibers in the corpus callosum

behavior/neurological

impaired balance ( J:176888 )

• mice develop motor deficits in the balance beam

impaired coordination ( J:176888 )

• mice develop motor deficits in the rotarod

growth/size/body

weight loss ( J:176888 )

• mice exhibit progressive weight loss

hematopoietic system

microgliosis ( J:176888 )

• mice show activated microglia in many brain regions

homeostasis/metabolism

increased brain cholesterol level ( J:176888 )

immune system

microgliosis ( J:176888 )

• mice show activated microglia in many brain regions

Genotype
MGI:5305067

cx13

• Allelic Composition: App^tm1Dbo/App^tm1Dbo; Npc1^m1N/Npc1^m1N
• Genetic Background: C.Cg-App^tm1Dbo Npc1^m1N

mortality/aging

premature death ( J:172769 )

• mutants start to die at 50 days of age

growth/size/body

weight loss ( J:172769 )

• 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

increased brain cholesterol level ( J:172769 )

• 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

decreased brain size ( J:172769 )

Purkinje cell degeneration ( J:172769 )

• lower number of surviving Purkinje cells in cerebellar lobes VIII and X

astrocytosis ( J:172769 )

• mutants exhibit a greater increase in astrocytosis and microglia activation than in single Npc1 homozygotes

demyelination ( J:172769 )

• mutants exhibit demyelination in the white matter

behavior/neurological

impaired coordination ( J:172769 )

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

homeostasis/metabolism

increased brain cholesterol level ( J:172769 )

• 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 Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Alzheimer's disease		DOID:10652		J:172769
Niemann-Pick disease		DOID:14504		J:172769

Genotype
MGI:2386740

cx14

• Allelic Composition: Abcb1a^tm1Bor/Abcb1a^tm1Bor; Npc1^m1N/Npc1^m1N
• Genetic Background: involves: 129/Ola * BALB/c

behavior/neurological

abnormal motor capabilities/coordination/movement ( J:76395 )

• neurological symptoms apparent and progressive, beginning at ~ day 50 of life

abnormal maternal nurturing ( J:76395 )

♀ • failed to care for pups

homeostasis/metabolism

increased liver cholesterol level ( J:76395 )

• cholesterol accumulation in liver

reproductive system

reproductive system phenotype ( J:76395 )

N • mice were fertile

liver/biliary system

increased liver cholesterol level ( J:76395 )

• cholesterol accumulation in liver

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Niemann-Pick disease		DOID:14504		J:76395

Genotype
MGI:3785902

cx15

• Allelic Composition: Apoe^tm1Unc/Apoe^tm1Unc; Npc1^m1N/Npc1^m1N
• Genetic Background: involves: 129P2/OlaHsd * BALB/c

homeostasis/metabolism

increased circulating VLDL cholesterol level ( J:104996 )

Genotype
MGI:3706954

cx16

• Allelic Composition: Npc1^m1N/Npc1^m1N; Tlr4^tm1Aki/Tlr4^tm1Aki
• Genetic Background: involves: 129P2/OlaHsd * BALB/c

immune system

abnormal cytokine secretion ( J:118352 )

• fibroblasts isolated from 6-week old double null mice secrete ~30% of levels in Tlr-4-sufficient, Npc1-null fibroblasts

nervous system

nervous system phenotype ( J:118352 )

N • number of activated glial cells in brains of double mutants is not different from Npc1-null brains

Genotype
MGI:4359170

cx17

• Allelic Composition: Abca1^tm1Wpfl/Abca1^tm1Wpfl; Npc1^m1N/Npc1^m1N
• Genetic Background: involves: 129P2/OlaHsd * BALB/c

mortality/aging

premature death ( J:130969 )

• mice die between 80 and 100 days of age from neurodegenerative disease

homeostasis/metabolism

decreased brain cholesterol level ( J:130969 )

• mice have decreased levels of total cholesterol in the brain

increased cholesterol level ( J:130969 )

• 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

decreased brain cholesterol level ( J:130969 )

• mice have decreased levels of total cholesterol in the brain

Genotype
MGI:3044885

cx18

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

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

mortality/aging

premature death ( J:89617 )

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

growth/size/body

weight loss ( J:89617 )

homeostasis/metabolism

abnormal lipid homeostasis ( J:89617 )

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

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

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

increased liver cholesterol level ( J:89617 )

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

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

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

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

nervous system

Purkinje cell degeneration ( J:89617 )

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

decreased Purkinje cell number ( J:89617 )

liver/biliary system

increased liver cholesterol level ( J:89617 )

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

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

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

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

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

Genotype
MGI:3706955

cx19

• Allelic Composition: Il6^tm1Kopf/Il6^tm1Kopf; Npc1^m1N/Npc1^m1N
• Genetic Background: involves: 129S2/SvPas * BALB/c * C57BL/6

nervous system

abnormal glial cell physiology ( J:118352 )

• nmber of activated microglial and astroglial cells is decreased in 6-week old mice compared to Il6-sufficient, Npc1-null mice

Genotype
MGI:4359169

cx20

• Allelic Composition: Npc1^m1N/Npc1^m1N; Nr1h2^tm1Djm/Nr1h2^tm1Djm
• Genetic Background: involves: 129S6/SvEvTac * BALB/c

mortality/aging

premature death ( J:130969 )

• 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		DO ID	OMIM ID(s)	Ref(s)
Niemann-Pick disease		DOID:14504		J:130969

Genotype
MGI:3785901

cx21

• Allelic Composition: Ldlr^tm1Her/Ldlr^tm1Her; Npc1^m1N/Npc1^m1N
• Genetic Background: involves: 129S7/SvEvBrd * BALB/c

mortality/aging

premature death ( J:130969 )

• mice die between 80 and 100 days of age from neurodegenerative disease

nervous system

decreased brain cholesterol level ( J:130969 )

• mice have decreased levels of total cholesterol in the brain

decreased corpus callosum size ( J:126474 )

• reduced in size by 50% at 11 weeks of age

• glial cells reduced by 44%

abnormal Purkinje cell axon morphology ( J:126474 )

• axonal swelling by 11 weeks of age

decreased Purkinje cell number ( J:126474 )

• small reduction in Purkinje cell numbers in the cerebellar hemispheres at 3 weeks of age

• reduction in numbers increases with age

abnormal CNS glial cell morphology ( J:126474 )

• glial cells in the corpus callosum reduced by 44%

homeostasis/metabolism

decreased brain cholesterol level ( J:130969 )

• mice have decreased levels of total cholesterol in the brain

increased cholesterol level ( J:130969 )

• 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

increased circulating LDL cholesterol level ( J:104996 , J:130969 )

• plasma LDL levels are increased 15-fold in these mice (J:130969)

Genotype
MGI:4367225

cx22

• Allelic Composition: Ldlr^tm1Her/Ldlr^tm1Her; Npc1^m1N/Npc1^m1N
• Genetic Background: involves: 129S7/SvEvBrd * BALB/c * C57BL/6

mortality/aging

premature death ( J:100351 )

• some early death among males on a high fat 1% cholesterol diet

liver/biliary system

increased liver weight ( J:100351 )

• 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

growth/size/body

increased liver weight ( J:100351 )

• 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

Genotype
MGI:5442379

cx23

• Allelic Composition: Npc1^m1N/Npc1^m1N; Tg(PRNP-APPSweInd)8Dwst/0
• Genetic Background: involves: BALB/c * C3H/HeJ * C57BL/6J

mortality/aging

premature death ( J:188345 )

• 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/body

decreased body weight ( J:188345 )

• mutants reach a maximum body weight of approximately 12 grams by 6 weeks of age which is about 30% less compared to controls

weight loss ( J:188345 )

• weight declines progressively after 6 weeks of age until death

behavior/neurological

abnormal object recognition memory ( J:188345 )

• 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

impaired coordination ( J:188345 )

• 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

decreased locomotor activity ( J:188345 )

• 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

microgliosis ( J:188345 )

• 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

increased brain cholesterol level ( J:188345 )

• 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

astrocytosis ( J:188345 )

• 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

neurodegeneration ( J:188345 )

• neurodgeneration in the cerebellum is accelerated compared to single Npc1 homozygotes

Purkinje cell degeneration ( J:188345 )

• 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

demyelination ( J:188345 )

• 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

microgliosis ( J:188345 )

• 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

abnormal enzyme/coenzyme level ( J:188345 )

• 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

increased brain cholesterol level ( J:188345 )

• 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

abnormal enzyme/coenzyme activity ( J:188345 )

• cathepsin D activity is higher in the hippocampus and the cerebellum than in controls, including single Npc1 homozygotes

immune system

microgliosis ( J:188345 )

• 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 Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Alzheimer's disease		DOID:10652		J:188345
Niemann-Pick disease		DOID:14504		J:188345

Genotype
MGI:3849460

cx24

• Allelic Composition: Npc1^m1N/Npc1^m1N; Tg(CAG-RAB9A)500Repa/0
• Genetic Background: involves: BALB/c * C57BL/6 * CBA

mortality/aging

premature death ( J:144240 )

• male mice have a 22% increase in lifespan compared to transgene-negative Npc1 homozygotes which die around 95 days of age

growth/size/body

decreased susceptibility to weight loss ( J:144240 )

• 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

abnormal phospholipid level ( J:144240 )

• 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