Phenotypes Associated with This Genotype

Genotype
MGI:5642030

• Allelic Composition: Npc1^tm1.1Dso/Npc1^tm1.1Dso
• Genetic Background: B6.129-Npc1^tm1.1Dso

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

mortality/aging

premature death ( J:221855 )

• mice have an average lifespan of 125 days; 59% longer than Npc1^m1N homozygotes

growth/size/body

decreased body weight ( J:221855 )

• lower body weight as compared to controls

weight loss ( J:221855 )

• progressive weight loss beginning at 10 weeks of age

homeostasis/metabolism

abnormal lipid homeostasis ( J:221855 )

• lipid storage in neocortex and liver

abnormal cholesterol homeostasis ( J:221855 )

abnormal sphingolipid level ( J:221855 )

• accumulation of multiple sphingolipid species in liver and brain tissue of older mice, principally monohexosylceramides and lactosylceramides

sphingomyelinosis ( J:221855 )

increased ceramide level ( J:221855 )

• lipid accumulation in P14 liver tissue includes: lactosylceramides, monohexosyceramides

increased lipid level ( J:221855 )

• lipid accumulation in P14 liver tissue includes: lactosylceramides, monohexosyceramides, sphingomyelins, sphingoid bases, gangiosides, unesterified cholesterol and 24(S)-hydroxycholesterol

increased brain cholesterol level ( J:221855 )

• subcellular storage of cholesterol in lobule X Purkinje neurons in P63 mice

• cholesterol accumulation within cell bodies and axonal segments of neocortical neurons

• cholesterol storage appears in all layers of the necortex, in particular V and VI

• most metabolites localize to neuronal cell bodies

• abnormal accumulation in meganeurites

increased liver cholesterol level ( J:221855 )

• cholesterol accumulation in hepatocytes and liver macrophages (CD68+)

• increase in unesterfied cholesterol in liver , but not brain, tissue of older mice

increased ganglioside level ( J:221855 )

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

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

• GM2 and GM3 ganglioside accumulation is less than in Npc1^m1N homozygotes

• ganglioside storage appears in all layers of the necortex, in particular V and VI

• most metabolites localize to neuronal cell bodies

• abnormal accumulation in meganeurites

behavior/neurological

tremors ( J:221855 )

• onset of resting tremor beginning at 8 weeks of age

impaired coordination ( J:221855 )

• mice cannot maintain balance on rotating rod by 12 weeks of age

nervous system

microgliosis ( J:221855 )

• microglial pathology in molecular, Purkinje cell and granular cell layers

abnormal microglial cell activation ( J:221855 )

• progression and spatial pattern is delayed in comparison to Npc1^m1N homozygotes

increased microglial cell activation ( J:221855 )

• age dependent increase in microglial activity

increased brain cholesterol level ( J:221855 )

• subcellular storage of cholesterol in lobule X Purkinje neurons in P63 mice

• cholesterol accumulation within cell bodies and axonal segments of neocortical neurons

• cholesterol storage appears in all layers of the necortex, in particular V and VI

• most metabolites localize to neuronal cell bodies

• abnormal accumulation in meganeurites

abnormal Purkinje cell morphology ( J:221855 )

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

Purkinje cell degeneration ( J:221855 )

• progressive, age-dependent Purkinje cell degeneration

• degree of loss is less severe at P63 than in Npc1^m1N homozygotes

• 58% reduction of Purkinje cells at P63 in anterior cerebella; 91% reduction by P105

• 65% reduction of Purkinje cells at P105 in posterior cerebella

• 88% reduction of Purkinje cells at P105 in central cerebella

• 41% reduction of Purkinje cells at P105 in nodular cerebella

• no observable loss in lobule X at P105

abnormal Purkinje cell dendrite morphology ( J:221855 )

• dystrophic dendritic abnormalities in cerebellar areas with Purkinje cell loss

astrocytosis ( J:221855 )

• age dependent increase in astrocyte reactivity

• progression and spatial pattern is delayed in comparison to Npc1^m1N homozygotes

axonal spheroids ( J:221855 )

• axonal spheroid formation in cerebellar areas with Purkinje cell loss

cellular

increased macrophage derived foam cell number ( J:221855 )

• liver macrophages exhibit a progressive foamy transformation

sphingomyelinosis ( J:221855 )

hematopoietic system

abnormal macrophage morphology ( J:221855 )

• polymembranous storage bodies found in liver macrophages

increased macrophage cell number ( J:221855 )

• increase in number of liver macrophages

increased macrophage derived foam cell number ( J:221855 )

• liver macrophages exhibit a progressive foamy transformation

microgliosis ( J:221855 )

• microglial pathology in molecular, Purkinje cell and granular cell layers

abnormal microglial cell activation ( J:221855 )

• progression and spatial pattern is delayed in comparison to Npc1^m1N 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

increased macrophage cell number ( J:221855 )

• increase in number of liver macrophages

increased macrophage derived foam cell number ( J:221855 )

• liver macrophages exhibit a progressive foamy transformation

microgliosis ( J:221855 )

• microglial pathology in molecular, Purkinje cell and granular cell layers

abnormal microglial cell activation ( J:221855 )

• progression and spatial pattern is delayed in comparison to Npc1^m1N 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 (CD68+)

• increase in unesterfied cholesterol in liver , but not brain, tissue of older mice

abnormal hepatocyte morphology ( J:221855 )

• polymembranous storage bodies found in hepatocytes

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Niemann-Pick disease		DOID:14504		J:221855