Phenotypes Associated with This Genotype

Genotype
MGI:3849202

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

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

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