Phenotypes Associated with This Genotype

Genotype
MGI:5305070

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

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

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

increased 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