Analysis Tools
mortality/aging
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• those that survive beyond the first few days grow normally until P18-P20 but generally die at about P35 in an emaciated condition
• attempts at keeping affected mice alive at greater than P35-P38 by forced feeding have been unsuccessful
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• a reduced number of homozygotes survive beyond a few days after birth (13% vs expected 25%); these die neonatally within a day or two of birth
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• a number of homozygotes appear to die in utero
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cellular
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• 37-day old males have a reduced number of late spermatids compared to wild-type and heterozygotes
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growth/size/body
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• BY ~P18-P20, affected homozygotes are slightly smaller than wild-type littermates
• at P35-P38, the body size of affected mice is less than 50% of wild-type littermates
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• mice are smaller than littermates at birth and by day 30, body weight is >50% of wild-type or heterozygotes
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• after birth mice gain less body weight than littermates
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reproductive system
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• 37-day old males have a reduced number of late spermatids compared to wild-type and heterozygotes
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• tubular diameter is smaller than wild-type
• at 25 and 30 days after birth, prostates of mutants are less developed and lined by an epithelium composed of short cells
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• prostatic epithelial cells in 37-day old males are shorter than those seen in controls
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• reduced in weight by 60%
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• glands have smaller tubular diameters and shorter undifferentiated epithelial cells
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• seminal vesicles are reduced in weight by 75%
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• testes are reduced in weight and size by 30% relative to wild-type controls
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• smaller tubular diameters and shorter undifferentiated epithelial cells are observed in epididymes
• epithelium lining the efferent ducts is made up of mainly ciliated cells in mutants whereas wild-type mice epithelium is majorly composed of nonciliated cells
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• reduced in weight by 37%
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nervous system
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• at >P30, intermittent seizures develop and progress to continual tonic status epilepticus
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• at P10, neuronal storage characterized by anti-ubiquitin Ab visualized granular immunoactivity becomes detectable in neuronal soma and neuropil of the spinal cord, and less prominently in brain stem and cerebrum
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• lamellar inclusions are seen in many ganglion cells in submucosal and myenteric plexi at P10, with myelin ovoids and abnormal Schwann cells similar to those in CNS and DRG after P20; axonal spheroids with dense bodies are also observed
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• choroid plexus epithelial cells contain inclusions detected at P10
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• the mutant white matter is pale and ill-defined from the grey matter, suggesting paucity of myelin
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• after P30, some astrocytes contains inclusions; inclusions are conspicuous in macrophages and consist of aggregates of small vesicular lamellar structures and electron-dense granules often bounded by a membrane
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astrocytosis
(
J:113052
)
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• astrocytes and microglia/macrophages are increased in numbers in cerebral and cerebellar white matter and fiber tracts of brain stem and spinal cord; after P30, increased numbers are detected in the gray matter
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• Schwann cells with foamy cytoplasm are found in trigeminal and sciatic nerves, as well as the dorsal and ventral roots; similar myelin changes are seen in dorsal and ventral roots
• after P20, cytoplasmic inclusions are found in Schwann cells of many myelinated fibers, and some unmyelinated fibers
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• at P1, few membrane-bound inclusions are detected, becoming more abundant with aging; after P30, storage neurons with foamy perikarya are conspicuous in the CNS
• spinal neurons contain many inclusions containing small vesicular or concentric lamellar structures admixed with granular structures by P10
• in cerebral cortical neurons, inclusions containing electron-dense granular or amorphous materials are more common than in spinal neurons
• membrane-bound dense bodies are found in the dendrites and axons in the cerebral cortex and spinal gray matter
• in cerebellum, inclusions are noted in granular cells but rarely in Purkinje cells before P20
• large inclusions consisting of granular or lamellar structures of various sizes and shapes are detected in many CNS neurons after P30
• after P30, cell bodies of CNS neurons contain heterogeneous storage materials, including eosinophilic and basophilic materials
• at P36, intramuscular nerves show Schwann cell changes like those observed in sciatic nerve
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• at P1, many neurons of DRG contain ubiquitin-positive granular inclusions, similar to the inclusions found in CNS and trigeminal ganglion of older mice
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• degenerating large axons with electron-dense amorphous material and lamellar structures are detected in CNS after P20
• paucity of myelin is detected in cerebral and cerebellar white matter and fiber tracts of brain stem and spinal cord after P30
• in peripheral nerves, some myelinated fibers exhibit degeneration but unmyelinated fibers are normal
• sciatic and trigeminal nerves show various stages of axonal degeneration and occasional paranodal swelling after day 36
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• axonal spheroids (localized axonal swellings) are detected in clusters in cerebral white matter adjacent to the striatum, ventral stria medullaris thalami, dorsal fornix, anterior commissure, and inferior cerebellar peduncle
• at P20, spheroids are mainly detected in the CNS white matter (spinal cord, brain stem, optic nerve) but increase in frequency in the gray matter after P30
• spheroids consist of axons filled with concentric or lamellar electron-dense bodies 0.1-0.3 um in diameter; after P20, many spheroids are covered with a myelin sheath
• some axonal spheroids are found at P20 in trigeminal and sciatic nerves; after P30, myelin ovoids increase
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demyelination
(
J:33477
)
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• at P30, homozygotes display severe hypomyelination and periodic acid-Schiff-positive materials throughout the nervous system and in abnormal cells in the liver and spleen
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behavior/neurological
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• food intake decreases after 30 days of age, coincident with development of neurological symptoms
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• by P30, homozygotes develop gross shaking of the trunk
(J:33477)
• around postnatal day 20 (P20), mice develop tremor, first noted in tail during walking and soon becoming generalized to whole body
(J:113052)
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• at ~P18-P20, homozygotes display tremulousness of the head
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head shaking
(
J:33477
)
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• by P28-P30, homozygotes exhibit gross shaking of the head
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• around postnatal day 20 (P20), mice develop gait disturbances
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• around postnatal day 20 (P20), mice begin to exhibit reduced activity
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• majority of mice display seizure-like hyperactivity after P30
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• hindlimb paralysis progresses slowly
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paraparesis
(
J:113052
)
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• after postnatal day 20 (P20), mice show progressive hindlimb weakness
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• at >P30, intermittent seizures develop and progress to continual tonic status epilepticus
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muscle
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• some fibers show membranous inclusions
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• majority of hindlimb girdle muscles become atrophic around P20
• skeletal muscles show occasional atrophic fibers on P36
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• by P30, homozygotes display severe weakness of all legs
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renal/urinary system
small kidney
(
J:33477
)
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• affected homozygotes display a significant reduction in kidney size
• no visceral organ abnormalities or organomegaly are observed
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• general weight reduction of 19%
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• many renal tubular epithelial cells have a granular appearance after P30
• proximal renal tubule epithelial cells have membranous inclusions at P10; at P30 many cells have electron-dense membrane-bound inclusions containing dense granules and small vesicular structures
• in older mice, inclusions are found in both proximal and distal tubule epithelial cells
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homeostasis/metabolism
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• levels are normal or higher in mutants relative to wild-type mice
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• activity of glucosylceramidase is about 60% that of wild-type mice
• total beta-hexaminidase activity is elevated
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• activity of GM1-ganglioside beta-galactosidase is elevated
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• at P30, predominantly lactosylceramide, as well as ceramide, glucosylceramide, galactosylceramide, sulfatide, and globotriaosylceramide are abnormally increased in brain, liver, and kidney; their catabolism is abnormally slow in cultured fibroblasts
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• at 40 days, brain levels of psychosine (galactosylsphingosine) is much lower (17.2 pmoL/mg) than in wild-type controls (34 pmol/mg)
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endocrine/exocrine glands
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• tubular diameter is smaller than wild-type
• at 25 and 30 days after birth, prostates of mutants are less developed and lined by an epithelium composed of short cells
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• prostatic epithelial cells in 37-day old males are shorter than those seen in controls
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• reduced in weight by 60%
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• glands have smaller tubular diameters and shorter undifferentiated epithelial cells
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• seminal vesicles are reduced in weight by 75%
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• testes are reduced in weight and size by 30% relative to wild-type controls
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hematopoietic system
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• in liver sinusoids, macrophages contain straight or curved loosely packed lamellar or small vesicular structures at P10; such structures increased in number and size markedly after P30 and often form tightly packed membranous conglomerates
• macrophages containing inclusions are found in the spleen at P10; after P30, macrophages with foamy periodic Schiff-positive cytoplasm increase in frequency in spleen
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• general weight reduction of 17%
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immune system
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• in liver sinusoids, macrophages contain straight or curved loosely packed lamellar or small vesicular structures at P10; such structures increased in number and size markedly after P30 and often form tightly packed membranous conglomerates
• macrophages containing inclusions are found in the spleen at P10; after P30, macrophages with foamy periodic Schiff-positive cytoplasm increase in frequency in spleen
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• general weight reduction of 17%
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liver/biliary system
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• some hepatocytes have lamellar and vesicular inclusions from P10
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• general weight reduction of 20%
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cardiovascular system
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• IN CNS, vesicular inclusions composed of many small vesicles are found in vascular endothelial cells after P20
• at P36 in lungs, some cells have inclusions
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vision/eye
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• neuronal inclusions in ganglion cells increase after P10
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• fibroblasts in corneal stroma show inclusions made up of granular and membranous structures at P36
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| combined saposin deficiency | DOID:0111330 |
OMIM:611721 |
J:33477 | |
