Mouse Genome Informatics
hm
    Npc1m1N/Npc1m1N
involves: BALB/c
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
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)

hematopoietic system
• 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
• progressive splenomegaly, beginning at 7 weeks of age

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
• elevation in lipid content in the lungs
• 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 in most organs except the brain at 7 weeks of age (J:104996)
• elevated in the brain at 1 day of age (J:104996)
• mice have increased cholesterol levels in the liver, spleen, intestine and lung (J:130969)
• 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)
• progressively increasing plasma cholesterol levels
• 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
• lipid accumulation (including sphingomyelin, glucocerebroside, lactosylceramide, and cholesterol) in various organs including the liver, lung, kidney, thymus, spleen, and brain (J:18511)
• at 7-8 weeks of age, female homozygotes show lipid accumulation in mural granulosa cells and in the ovarian stroma, as shown by oil-red-O staining (J:91430)
• lungs exhibit surfactant accumulation, indicating alveolar lipidosis (J:204311)
• proteinaceous-like material in the alveolar space
• mild protein accumulation in bronchoalveolar lavage

immune system
• 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
• progressive splenomegaly, beginning at 7 weeks of age

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
• in vitro, 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 (J:119302)
• 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 (J:119302)
• interestingly, 30% of total cyritestin protein is not proteolytically processed on mutant cauda sperm, whereas fertilin beta is processed normally (J:119302)
• some mutant seminiferous tubules exhibit evidence of extensive degeneration (J:119302)
• adult mutant ovaries show near absence of 17beta-estradiol (E2) content (2.0 pg) relative to 110-135 pg/ovary in wild-type controls (J:91430)
• expression of two key steroidogenic proteins (StAR and Cyp19) is markedly reduced in mutant ovaries relative to wild-type controls (J:91430)
• however, exogenous gonadotropin treatment restores expression of both steroidogenic proteins to wild-type levels (J:91430)
• at 7-8 weeks of age, female homozygotes exhibit a thinner reproductive tract than wild-type females (J:91430)
• at 7-8 weeks of age, reduction in the endometrial stroma is associated with a reduction in the convolution of uterine glands (J:91430)
• at 7-8 weeks of age, the stromata of mutant ovaries contain numerous islands of foamy cells composed of healthy nuclei and vacuolated cytoplasm (J:91430)
• these cell nests are replete with lipid, as shown by oil-red-O staining (J:91430)
• at 7-8 weeks of age, no formation of corpora lutea is observed (J:91430)
• 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 (J:91430)
• at 7 weeks of age, mutant ovarian follicles and stromata exhibit lipid accumulation, as shown by oil-red-O staining (J:91430)
• at 7-8 weeks of age, mutant mural granulosa cells exhibit lipid accumulation, as shown by oil-red-O staining (J:91430)
• mutant ovarian follicles fail to mature to the large antral and preovulatory stages (J:91430)
• at 7 weeks of age, mutant antral follicles are smaller than the largest follicles found in wild-type controls (J:91430)
• the number of mutant secondary and antral follicles is reduced relative to wild-type controls (J:91430)
• 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 (J:91430)
• chronic treatment of 8-wk-old female mutants with 17beta-estradiol (E2) increases the number of secondary and large antral follicles, well in excess of that found in untreated mutant ovaries (J:91430)
• at 7-8 weeks, but not at 3 weeks, of age mutant ovaries are smaller than wild-type (J:91430)
• 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 (J:91430)
• at 8 weeks of age, a reduction in endometrial thickness is observed (J:91430)
(J:91430)
• at 7-8 weeks of age, mutant uteri are thinner than wild-type (J:91430)
• at 7-8 weeks of age, atrophy of the myometrium, endometrial stroma, and the endometrial epithelium is observed (J:91430)
• at 60 days of age, the total number of mutant cauda sperm is reduced to only ~28% of that in wild-type males (J:119302)
• 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) (J:119302)
• at 60 days of age, tailless sperm heads are frequently observed (J:119302)
• at 60 days of age, aberrant cauda sperm heads are frequentyly observed (J:119302)
• at 60 days of age, headless sperm tails are frequently observed (J:119302)
• 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 (J:119302)
• at 7-8 weeks of age, mutant ovaries display no evidence of ovulation (J:91430)
• 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 (J:91430)
• mutant ovaries transplanted under wild-type kidney capsules display evidence of ovulation, as shown by the presence of corpora lutea and an extraovarian oocyte (J:91430)
• female homozygotes are acyclic (J:91430)
• females showed normal oogenesis, but lacked implantation sites after successful plugging
• female homozygotes are infertile (J:91430)
• male homozygotes are infertile (J:119302)
• 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

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
• 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
• 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
• 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)
• 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)
• 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
• axonal swelling by 11 weeks of age
• localized axonal swellings, malformations of the dendritic arbor, and accumulation of vesicular storage materials within the cytoplasm
• 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, tailless sperm heads are frequently observed (J:119302)
• higher rate of turnover although whole body pool is considerably elevated
• rate of cholesterol synthesis is reduced
• in vitro, 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 (J:119302)
• 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 (J:119302)
• interestingly, 30% of total cyritestin protein is not proteolytically processed on mutant cauda sperm, whereas fertilin beta is processed normally (J:119302)

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 (J:91430)
• at 7-8 weeks of age, the stromata of mutant ovaries contain numerous islands of foamy cells composed of healthy nuclei and vacuolated cytoplasm (J:91430)
• these cell nests are replete with lipid, as shown by oil-red-O staining (J:91430)
• at 7-8 weeks of age, no formation of corpora lutea is observed (J:91430)
• 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 (J:91430)
• at 7 weeks of age, mutant ovarian follicles and stromata exhibit lipid accumulation, as shown by oil-red-O staining (J:91430)
• at 7-8 weeks of age, mutant mural granulosa cells exhibit lipid accumulation, as shown by oil-red-O staining (J:91430)
• mutant ovarian follicles fail to mature to the large antral and preovulatory stages (J:91430)
• at 7 weeks of age, mutant antral follicles are smaller than the largest follicles found in wild-type controls (J:91430)
• the number of mutant secondary and antral follicles is reduced relative to wild-type controls (J:91430)
• 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 (J:91430)
• chronic treatment of 8-wk-old female mutants with 17beta-estradiol (E2) increases the number of secondary and large antral follicles, well in excess of that found in untreated mutant ovaries (J:91430)
• at 7-8 weeks, but not at 3 weeks, of age mutant ovaries are smaller than wild-type (J:91430)
• 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 (J:91430)
• some mutant seminiferous tubules exhibit evidence of extensive degeneration (J:119302)
• adult mutant ovaries show near absence of 17beta-estradiol (E2) content (2.0 pg) relative to 110-135 pg/ovary in wild-type controls (J:91430)
• expression of two key steroidogenic proteins (StAR and Cyp19) is markedly reduced in mutant ovaries relative to wild-type controls (J:91430)
• however, exogenous gonadotropin treatment restores expression of both steroidogenic proteins to wild-type levels (J:91430)

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
OMIM IDRef(s)
Niemann-Pick Disease, Type C1; NPC1 257220 J:18511 , J:76733 , J:81305 , J:130969 , J:204311