Mouse Genome Informatics
hm
    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)
• architecture of olfactory receptor neurons is disturbed, showing enlarged gap-like spaces in the basal and middle portions of the epithelium
• 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
• decrease in brain weight of old mice
• 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
• the olfactory bulb shows increased expression of galectin-3, particularly in the glomerular cell layer, indicating increased inflammatory processes
• astrocytosis in the olfactory bulb, particularly within the glomerular layer
• myelin-like deposits in trigeminal ganglion cells and satellite cells
• 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)
• peripheral and central neurodgeneration in the olfactory system
• 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
• marker analysis indicates an increase in lysosomal activity and lipid efflux

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
• 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
• architecture of olfactory receptor neurons is disturbed, showing enlarged gap-like spaces in the basal and middle portions of the epithelium
• adults, but not young mice, show reduced body weight
• significant weight loss observed at 6-7 weeks of age as compared to controls

hematopoietic system
• 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
• 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
• 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
• 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
• 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
• 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

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

respiratory system
• 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
• architecture of olfactory receptor neurons is disturbed, showing enlarged gap-like spaces in the basal and middle portions of the epithelium
• 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
• 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
• 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
• architecture of olfactory receptor neurons is disturbed, showing enlarged gap-like spaces in the basal and middle portions of the epithelium
• 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
OMIM IDRef(s)
Niemann-Pick Disease, Type C1; NPC1 257220 J:182268 , J:209834