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Phenotypes Associated with This Genotype
Genotype
MGI:2386738
Allelic
Composition
Npc1m1N/Npc1m1N
Genetic
Background
involves: BALB/c
Find Mice Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Npc1m1N mutation (3 available); any Npc1 mutation (74 available)
phenotype observed in females
phenotype observed in males
N normal phenotype

Abnormal morphology of Npc1m1N/Npc1m1N sperm

mortality/aging
• ~75 day life span (J:81305)
• mice die between 80 and 100 days of age from neurodegenerative disease (J:130969)

behavior/neurological
• poor food intake, beginning at 7 weeks of age
• defects beginning at 7 to 8 weeks of age
• mice exhibit impaired coordination around 40 days of age with coordination worsening as the mice age

growth/size/body
• female homozygotes display a smaller stature than wild-type females
• female homozygotes display a reduced body mass relative to wild-type females (J:91430)
• beginning at 7 to 8 weeks of age (J:76733)
• mice exhibit weight loss starting at 40 days of age (J:130969)
• 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)
• hepatomegaly and associated pale liver, presumably due to lipid accumulation
• progressive increase in liver weight, beginning at 7 weeks of age
• progressive splenomegaly, beginning at 7 weeks of age

hematopoietic system
• progressive splenomegaly, beginning at 7 weeks of age
• 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
• higher rate of turnover although whole body pool is considerably elevated
• rate of cholesterol synthesis is reduced
• female homozygotes show a 25% increase in serum FSH levels relative to wild-type controls
• 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
• 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
• female homozygotes show a dramatic reduction in serum prolactin levels relative to wild-type controls
• 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)
• 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
• elevation in lipid content in the lungs
• elevated in most organs except the brain at 7 weeks of age (J:104996)
• mice have increased cholesterol levels in the liver, spleen, intestine and lung (J:130969)
• progressively increasing plasma cholesterol levels
• elevated cholesterol level in the brain at 1 day of age
• 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)
• 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)
• proteinaceous-like material in the alveolar space
• mild protein accumulation in bronchoalveolar lavage

immune system
• progressive splenomegaly, beginning at 7 weeks of age
• 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
• hepatomegaly and associated pale liver, presumably due to lipid accumulation
• progressive increase in liver weight, beginning at 7 weeks of age
• massive liver storage of cholesterol in mice on a high fat, 1% cholesterol diet

reproductive system
• at 60 days of age, the total number of mutant cauda sperm is reduced to only ~28% of that in wild-type males
• 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)
• at 60 days of age, tailless sperm heads are frequently observed
• at 60 days of age, aberrant cauda sperm heads are frequentyly observed
• at 60 days of age, headless sperm tails are frequently observed
• some mutant seminiferous tubules exhibit evidence of extensive degeneration
• 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
• at 7-8 weeks of age, female homozygotes exhibit a thinner reproductive tract than wild-type females
• at 7-8 weeks of age, reduction in the endometrial stroma is associated with a reduction in the convolution of uterine glands
• 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
• 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
• at 7 weeks of age, mutant ovarian follicles and stromata exhibit lipid accumulation, as shown by oil-red-O staining
• at 7-8 weeks of age, mutant mural granulosa cells exhibit lipid accumulation, as shown by oil-red-O staining
• mutant ovarian follicles fail to mature to the large antral and preovulatory stages
• 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
• 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
• 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
• at 7-8 weeks, but not at 3 weeks, of age mutant ovaries are smaller than wild-type
• 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
• at 8 weeks of age, a reduction in endometrial thickness is observed
• at 7-8 weeks of age, mutant uteri are thinner than wild-type
• at 7-8 weeks of age, atrophy of the myometrium, endometrial stroma, and the endometrial epithelium is observed
• 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
• 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
• 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
• female homozygotes are acyclic
• females showed normal oogenesis, but lacked implantation sites after successful plugging
• female homozygotes are infertile
• male homozygotes are infertile
• 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
• 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
• 30% of total cyritestin protein is not proteolytically processed on mutant cauda sperm, whereas fertilin beta is processed normally

respiratory system
• lungs contain 'nests' of vacuolar filled macrophages and enlarged foamy alveolar macrophages
• 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
• 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)
• 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
• 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)
• proteinaceous-like material in the alveolar space
• mild protein accumulation in bronchoalveolar lavage
• alveolar type II cells have many autophagosomes
• cholesterol and phospholipid accumulation in lamellar bodies of alveolar type II cells
• 42% of alveolar type II cell lamellar bodies are enlarged compared to 15% in wild-type mice
• thickening of the intra-alveolar septae with a slight enlargement of the airways
• liposome degradation is reduced by 46% in the lungs
• increase in surfactant phospholipid levels

nervous system
• the mutant anterior pituitary displays vacuolated cells, suggestiing low rates of feedback control and increased hormone synthesis and secretion
• 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
• the mutant anterior pituitary is hypoplastic relative to wild-type
• 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)
• elevated cholesterol level in the brain at 1 day of age
• progressive decrease in brain weight, beginning at 7 weeks of age (J:76733)
• brain weight is lower than in controls mice (J:130969)
• reduced in size by 50% at 11 weeks of age
• glial cells reduced by 52%
• by P45, Purkinje cell loss was most evident in the anterior cerebellar vermis
• degenerating cells belonged preferentially to the zebrin II-negative subtype
• 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
• cerebellum weight is smaller than controls
• glial cells in the corpus callosum reduced by 52%
• vacuolated cytoplasmic storage material in all regions of the central nervous system
• localized axonal swellings, malformations of the dendritic arbor, and accumulation of vesicular storage materials within the cytoplasm
• axonal swelling by 11 weeks of age
• 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)
• reduced levels of both myelin protein and myelin cholesterol

cellular
• at 60 days of age, the total number of mutant cauda sperm is reduced to only ~28% of that in wild-type males
• 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)
• at 60 days of age, tailless sperm heads are frequently observed
• at 60 days of age, aberrant cauda sperm heads are frequentyly observed
• at 60 days of age, headless sperm tails are frequently observed
• Golgi fragmentation is found in neurons of the cerebral cortex, cerebellar Purkinje cells, and brainstem neurons
• higher rate of turnover although whole body pool is considerably elevated
• rate of cholesterol synthesis is reduced

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

endocrine/exocrine glands
• the mutant anterior pituitary displays vacuolated cells, suggestiing low rates of feedback control and increased hormone synthesis and secretion
• 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
• the mutant anterior pituitary is hypoplastic relative to wild-type
• at 7-8 weeks of age, reduction in the endometrial stroma is associated with a reduction in the convolution of uterine glands
• 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
• 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
• at 7 weeks of age, mutant ovarian follicles and stromata exhibit lipid accumulation, as shown by oil-red-O staining
• at 7-8 weeks of age, mutant mural granulosa cells exhibit lipid accumulation, as shown by oil-red-O staining
• mutant ovarian follicles fail to mature to the large antral and preovulatory stages
• 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
• 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
• 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
• at 7-8 weeks, but not at 3 weeks, of age mutant ovaries are smaller than wild-type
• 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
• some mutant seminiferous tubules exhibit evidence of extensive degeneration
• 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
• 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


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last database update
10/29/2024
MGI 6.24
The Jackson Laboratory