Analysis Tools
mortality/aging
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• only ~30% of mice survive to 60 weeks of age
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• progressive decline in survival falling below 50% by 40 weeks of age
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• homozygotes are born with a reduced frequency (15% versus expected 25%), suggesting reduced in utero survival
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growth/size/body
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• facial dysmorphism is evident from birth and progresses with age
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• reduced nasal bridge evident from birth
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• flat profile with reduced nasal bridge evident from birth
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• mice remain significantly smaller than wild-type controls (~60%) throughout life
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• body weight progression is significantly reduced starting at 8 weeks of age
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craniofacial
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• facial dysmorphism is evident from birth and progresses with age
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• reduced nasal bridge evident from birth
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• flat profile with reduced nasal bridge evident from birth
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vision/eye
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• progressive thickening of the eyelids evident from birth
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skeleton
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• skeletal abnormalities are evident from birth
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• severe deformities affecting the spine at 12 months of age
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• mutant tracheal cartilage chondrocytes are enlarged with their cytoplasm filled by inclusion bodies and abundant microvacuoles, unlike wild-type chondrocytes which show low basic cytoplasm containing a single clear vacuole
• mutant chondrocytes are less affected by fixation-induced shrinkage than wild-type chondrocytes
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behavior/neurological
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• mice show a 50% alternation in choosing an arm at random in the Y-maze spontaneous alternation task, indicating deficits in psychomotor performance (cognitive slownes)
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• limb-clasping reflexes starting at 5 months of age
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• ataxic gait confirmed by Noldus Catwalk automated gait analysis, with a progressive and highly significant reduction of the regularity index (a measure of regular footstep pattern) noted between 6 and 12 months of age
• front paw base of support is significantly increased from 3 months of age
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• reduced motor balance and coordination on the rotarod at 3, 6, and 12 months of age
• rotarod performance worsens with age
• weekly injection of P7 mice with 2-hydroxypropyl-beta-cyclodextrin for 7 months does not improve rotarod performance at 3 months or at 7 months of age
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• progressive gait abnormality
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nervous system
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• increased inflammatory response as shown by increased GFAP immunoreactivity throughout the whole brain
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• brain is about 30% smaller than normal
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• luxol fast blue staining of cerebellar sections indicates reduced myelination and degeneration of the subcortical white matter
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• increased glycolipid storage in hippocampal layer CA1 at 9 months of age
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• increased glycolipid storage in hippocampal layer CA3 at 9 months of age
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• large amounts of storage of glycolipids in cortical layers III-IV with lesser amounts in layers I and II at 9 months of age
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• progressive Purkinje cell degeneration with ~25% and ~50% Purkinje cell loss at 7 and 11 months of age, respectively
• cell death is often accompanied by an inflammatory response and a defect in myelination
• however, majority of Purkinje cells in lobe IV/V are still present at 3 months
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• swelling of Purkinje cell axons and neuronal torpedoes typical of cell atrophy are already detected at 3 months and increase in severity with age
• axonal spheroids/torpedoes precede Purkinje cell loss
• weekly injection of P7 mice with 2-hydroxypropyl-beta-cyclodextrin for 7 months does not rescue or delay the signs of Purkinje cell degeneration (swelling of dendrites and axonal torpedoes) at 3 months or at 7 months of age
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• increased storage of glycolipids in the cerebellar molecular layer relative to the granule layer at 9 months of age
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• brain atrophy worsens over time
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astrocytosis
(
J:218156
)
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• increased GFAP immunoreactivity throughout the whole brain, mostly affecting the cerebellum
• marked astrogliosis in the cerebellar white matter, granule layer, and Purkinje cell layer
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• axonal spheroid formation at 3 months that worsens with age
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• demyelination of the cerebellum with thinning of the white matter tracts
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muscle
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• reduced muscle strength on the inverted screen test at 3, 6, and 12 months of age
• inverted screen performance worsens with age
• weekly injection of P7 mice with 2-hydroxypropyl-beta-cyclodextrin for 7 months does not improve inverted screen performance at 3 months or at 7 months of age
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endocrine/exocrine glands
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• marked disorganization of pancreatic tissue structure
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• enlargement of pancreatic acinar cells due to presence of large vacuoles containing faint granular material
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cellular
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• accumulation of inclusion bodies indicative of lysosomal storage in mouse embryonic fibroblasts, secretory tissue (pancreatic acinar cells) and connective tissue (tracheal cartilage chondrocytes)
• inclusions are aggregates of polysaccharides that increase in storage material with age
• deregulation of lysosomal enzymes leading to increased glycolipid and cholesterol storage in the cerebellum, cortex, and hippocampus at 9 months of age
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homeostasis/metabolism
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• at 3 months of age, serum enzymatic activities of the lysosomal hydrolases beta-hexosaminidase, beta-galactosidase, alpha-mannosidase, and beta-mannosidase are increased by 2.5- to 30-fold relative to wild-type controls
• at 4 months of age, enzymatic activities of beta-hexosaminidase, alpha-mannosidase, and beta-glucoronidase are increased by 1.5-fold, whereas beta-galactosidase is decreased by 30%, as measured in whole brain lysates
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integument
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• unusually stiff skin
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thick skin
(
J:218156
)
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• unusually thick skin
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immune system
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• increased inflammatory response as shown by increased GFAP immunoreactivity throughout the whole brain
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reproductive system
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• increased frequency of males with penile prolapse starting at 3 months of age
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• mating is only successful in 9% of breeding pairs, indicating infertility or incapacity of females to carry pups to term
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digestive/alimentary system
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• enlargement of pancreatic acinar cells due to presence of large vacuoles containing faint granular material
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renal/urinary system
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• increased frequency of males with penile prolapse starting at 3 months of age
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respiratory system
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• reduced nasal bridge evident from birth
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| mucolipidosis II alpha/beta | DOID:0080070 |
OMIM:252500 |
J:218156 | |
