Analysis Tools
mortality/aging
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• ~75 day life span
(J:81305)
• mice die between 80 and 100 days of age from neurodegenerative disease
(J:130969)
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behavior/neurological
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• poor food intake, beginning at 7 weeks of age
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• defects beginning at 7 to 8 weeks of age
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• mice exhibit impaired coordination around 40 days of age with coordination worsening as the mice age
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growth/size/body
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• female homozygotes display a smaller stature than wild-type females
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• female homozygotes display a reduced body mass relative to wild-type females
(J:91430)
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• beginning at 7 to 8 weeks of age
(J:76733)
• mice exhibit weight loss starting at 40 days of age
(J:130969)
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• 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)
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• hepatomegaly and associated pale liver, presumably due to lipid accumulation
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• progressive increase in liver weight, beginning at 7 weeks of age
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• progressive splenomegaly, beginning at 7 weeks of age
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hematopoietic system
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• progressive splenomegaly, beginning at 7 weeks of age
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• 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
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homeostasis/metabolism
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• higher rate of turnover although whole body pool is considerably elevated
• rate of cholesterol synthesis is reduced
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• female homozygotes show a 25% increase in serum FSH levels relative to wild-type controls
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• 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
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• 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
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• female homozygotes show a dramatic reduction in serum prolactin levels relative to wild-type controls
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• elevation in lipid content in the lungs
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• 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)
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• 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)
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• progressively increasing plasma cholesterol levels
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• 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
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• 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)
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• proteinaceous-like material in the alveolar space
• mild protein accumulation in bronchoalveolar lavage
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immune system
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• progressive splenomegaly, beginning at 7 weeks of age
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• 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
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liver/biliary system
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• hepatomegaly and associated pale liver, presumably due to lipid accumulation
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• progressive increase in liver weight, beginning at 7 weeks of age
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• massive liver storage of cholesterol in mice on a high fat, 1% cholesterol diet
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pale liver
(
J:91430
)
reproductive system
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• at 60 days of age, the total number of mutant cauda sperm is reduced to only ~28% of that in wild-type males
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• 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)
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• at 60 days of age, tailless sperm heads are frequently observed
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• at 60 days of age, aberrant cauda sperm heads are frequentyly observed
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• at 60 days of age, headless sperm tails are frequently observed
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• some mutant seminiferous tubules exhibit evidence of extensive degeneration
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• 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
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• at 7-8 weeks of age, female homozygotes exhibit a thinner reproductive tract than wild-type females
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• at 7-8 weeks of age, reduction in the endometrial stroma is associated with a reduction in the convolution of uterine glands
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• 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
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• 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
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• at 7 weeks of age, mutant ovarian follicles and stromata exhibit lipid accumulation, as shown by oil-red-O staining
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• at 7-8 weeks of age, mutant mural granulosa cells exhibit lipid accumulation, as shown by oil-red-O staining
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• mutant ovarian follicles fail to mature to the large antral and preovulatory stages
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• 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
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• 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
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• 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
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small ovary
(
J:91430
)
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• at 7-8 weeks, but not at 3 weeks, of age mutant ovaries are smaller than wild-type
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• 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
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• at 8 weeks of age, a reduction in endometrial thickness is observed
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thin uterus
(
J:91430
)
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• at 7-8 weeks of age, mutant uteri are thinner than wild-type
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• at 7-8 weeks of age, atrophy of the myometrium, endometrial stroma, and the endometrial epithelium is observed
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• 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
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• 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
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anovulation
(
J:91430
)
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• 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
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• female homozygotes are acyclic
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infertility
(
J:76395
)
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• females showed normal oogenesis, but lacked implantation sites after successful plugging
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• female homozygotes are infertile
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• male homozygotes are infertile
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• 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
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• 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
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• 30% of total cyritestin protein is not proteolytically processed on mutant cauda sperm, whereas fertilin beta is processed normally
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respiratory system
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• lungs contain 'nests' of vacuolar filled macrophages and enlarged foamy alveolar macrophages
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• 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
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• 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)
|
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• 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
|
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• proteinaceous-like material in the alveolar space
• mild protein accumulation in bronchoalveolar lavage
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• alveolar type II cells have many autophagosomes
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• cholesterol and phospholipid accumulation in lamellar bodies of alveolar type II cells
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• 42% of alveolar type II cell lamellar bodies are enlarged compared to 15% in wild-type mice
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• thickening of the intra-alveolar septae with a slight enlargement of the airways
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• liposome degradation is reduced by 46% in the lungs
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• increase in surfactant phospholipid levels
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nervous system
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• the mutant anterior pituitary displays vacuolated cells, suggestiing low rates of feedback control and increased hormone synthesis and secretion
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• 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
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• the mutant anterior pituitary is hypoplastic relative to wild-type
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• 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)
|
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• progressive decrease in brain weight, beginning at 7 weeks of age
(J:76733)
• brain weight is lower than in controls mice
(J:130969)
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• reduced in size by 50% at 11 weeks of age
• glial cells reduced by 52%
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• by P45, Purkinje cell loss was most evident in the anterior cerebellar vermis
• degenerating cells belonged preferentially to the zebrin II-negative subtype
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• 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
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• cerebellum weight is smaller than controls
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• glial cells in the corpus callosum reduced by 52%
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• vacuolated cytoplasmic storage material in all regions of the central nervous system
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• localized axonal swellings, malformations of the dendritic arbor, and accumulation of vesicular storage materials within the cytoplasm
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• axonal swelling by 11 weeks of age
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• 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)
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• reduced levels of both myelin protein and myelin cholesterol
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cellular
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• at 60 days of age, the total number of mutant cauda sperm is reduced to only ~28% of that in wild-type males
|
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• 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)
|
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• at 60 days of age, tailless sperm heads are frequently observed
|
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• at 60 days of age, aberrant cauda sperm heads are frequentyly observed
|
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• at 60 days of age, headless sperm tails are frequently observed
|
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• Golgi fragmentation is found in neurons of the cerebral cortex, cerebellar Purkinje cells, and brainstem neurons
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• higher rate of turnover although whole body pool is considerably elevated
• rate of cholesterol synthesis is reduced
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adipose tissue
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• female homozygotes exhibit reduced abdominal fat deposits relative to wild-type females
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endocrine/exocrine glands
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• the mutant anterior pituitary displays vacuolated cells, suggestiing low rates of feedback control and increased hormone synthesis and secretion
|
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• however, chronic (4-week) treatment with 17beta-estradiol (E2) restores pituitary volume and acidophil numbers to wild-type levels
• the mutant anterior pituitary shows a dramatic reduction in acidophil cell number relative to wild-type
|
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• the mutant anterior pituitary is hypoplastic relative to wild-type
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• 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
|
small ovary
(
J:91430
)
|
|
• 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 | ||
