Mouse Genome Informatics
hm1
    Galctwi/Galctwi
B6.CE-Galctwi/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• Background Sensitivity: lifespan of mutants is 45.5 days; death is result of peripheral and cranial nerve palsy (J:108359)
• Background Sensitivity: the average lifespan of homozygotes in this study is 37 days (J:126892)
• median survival is 51 days (J:170081)

homeostasis/metabolism
• IGF-1 plasma levels are reduced by 37.6%
• galactosylsphingosine accumulation, with 14 fold higher levels than in wild-type, in the long bones
• increase in total sphingomyelin in femurs, and in most of the sphingomyelin and ceramide containing saturated-unsaturated fatty acids
• levels of Ptgds2 activity are 3-fold higher in the cerebrum and 5-fold higher in the cerebellum of mutants compared to wild-type

behavior/neurological
• mutants have poorer righting response compared to wild-type or Ptgds2/Galc double mutants
• mutants barely stagger with strong intentional tremor (J:108359)
• Background Sensitivity: mean age of onset 21 days (J:126892)
• Background Sensitivity: wobbly gait appears at approximately 28-30 days of age
• moribund mice develop spastic paresis

nervous system
• microglia in mutant brains have increased levels of Ptgds2 protein and have irregular thick processes in the region of demyelination
• Background Sensitivity: lectin-positive macrophages are found in the cerebellum, pons, and medulla more severely on this genetic background than when outcrossed to CAST/EiJ
• mutants exhibit an increase in oligodendrocyte progenitor cell (OPC) population compared to wild-type
• levels of psychosine are increased in the forebrain while levels of free sphingosine are lower compared to wild-type mice
• dramatically increased concentration of psychosine in the pons/medulla which is not impacted by genetic background
• there are hypertrophied astrocytes with large soma and thick-branched processes in mutant brains (J:108359)
• Background Sensitivity: increased GFAP staining astrocytes are found in the cerebellar granular layer and pons (J:126892)
• white matter exhibits similar reactive astrocytosis as double Galctwi Csf1op mice
• oligodendrocyte progenitor cells become hypertrophic and have short and stout processes instead of well branched fine processes as in wild-type mice
• mutants exhibit a moderate decrease in oligodendrocytes
• sciatic nerves are swollen and demyelination and myelin debris is found in moribund homozygotes
• 39 day-old mutant brains exhibit demyelination; demyelination appears to be restricted to the CNS (J:108359)
• Background Sensitivity: extensive demyelination is found in the cerebellar white matter at the moribund stage on this genetic background (J:126892)
• myelin degeneration in the white matter, with a preferential loss of myelin in large diameter axons (J:170081)
• sciatic nerves are severely demyelinated (J:170081)
• however, development (wrapping) of myelin from P15 to P30 is not affected (J:170081)

hematopoietic system
• microglia in mutant brains have increased levels of Ptgds2 protein and have irregular thick processes in the region of demyelination
• enhanced osteoclast activity

immune system
• microglia in mutant brains have increased levels of Ptgds2 protein and have irregular thick processes in the region of demyelination
• enhanced osteoclast activity

growth/size
• body weight is reduced starting at P20
• mutants start to lose weight after P35

limbs/digits/tail
• femurs are smaller and weigh 27% less than wild-type femurs at 32-33 days of age

skeleton
• femurs are smaller and weigh 27% less than wild-type femurs at 32-33 days of age
• metaphyseal region of femurs show structural differences, with reduced trabecular bone mainly in the secondary spongiosa
• mice exhibit features of osteopenia
• decrease in cortical bone thickness in femurs
• decrease in the number of trabeculae in femurs
• growth of long bones is retarded
• reduction of bone deposition in the metaphyseal and epiphyseal region of femurs, but no differences in mineral apposition rate
• enhanced osteoclast activity

muscle
• mutants develop fine twitching in the neck around P20

Mouse Models of Human Disease
OMIM IDRef(s)
Krabbe Disease 245200 J:6390 , J:6423 , J:165361 , J:170081


Mouse Genome Informatics
hm2
    Galctwi/Galctwi
CE/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• demonstrated by light and electron microscopic investigations
• demonstrated by light and electron microscopic investigations
• this mutation is the first spontaneous model for endoneurial edema and increased endoneurial fluid pressure
• mice show greater macrophage infiltration than Psaptm1Suz mice
• mice show more severe demyelination than do homozygous Psaptm1Suz mice (J:78223)
• some degeneration is evident by light and electron microscopic investigations
• both motor and sensory nerves are involved

immune system
• mice show greater macrophage infiltration than Psaptm1Suz mice

homeostasis/metabolism
• endoneurial edema contributing to increased endoneurial fluid pressure
• 45-day old mice have a much greater accumulation of galactosylceramide in kidney is greater than in 4-month old Psap-deficient mice
• at 40 days, brain levels of psychosine (galactosylsphingosine) are much higher than in wild-type controls or Psap-deficient mice (223 pmol/mg vs 60 or 32 pmol/mg)

behavior/neurological
• clinically evident between 15 and 20 days of age, beginning as a fine tremor
• involves the whole body
• particularly the hindlimbs
• evident by terminal stages of the disease

growth/size
• mutant mice are smaller than normal siblings especially noticeable between 15 and 20 days of age


Mouse Genome Informatics
hm3
    Galctwi/Galctwi
involves: 129P2/OlaHsd * C57BL/6J * CE/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• Background Sensitivity: average lifespan 48 days of age with nearly all dead before 58 days of age


Mouse Genome Informatics
hm4
    Galctwi/Galctwi
involves: C57BL/6J * CAST/EiJ * CE/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• Background Sensitivity: average lifespan is 61.4 days on this mixed genetic background, longer than on the congenic C57BL/6J background, and there is much wider variation in the life span of individuals, which ranges from 45 to 77 days

behavior/neurological
• Background Sensitivity: mean age of tremor onset is 24 days which is delayed when compared with homozygotes on a congenic C57BL/6J background, which have a mean age of onset of 21 days
• Background Sensitivity: the longer lived homozygotes display more severe wasting of the hindlimbs when at moribund conditions than do those on a C57BL/6J congenic background
• Background Sensitivity: wobbly gait does not develop until 30 days of age or beyond which is delayed compared with the congenic C57BL/6J background on which a wobbly gait appears at approximately 28-30 days of age

nervous system
• lectin-positive macrophages are found in the cerebellum, pons, and medulla in the moribund stage, although to a lesser degree than in homozygotes on a C57BL/6J congenic background
• on both this mixed genetic background and on the congenic C57BL/6J background the concentration of psychosine in the pons/medulla is dramatically higher than normal and the level of increase is not impacted by genetic background
• Background Sensitivity: increased GFAP staining astrocytes are found in the cerebellar granular layer to a greater degree on this mixed genetic background than homozygotes on the congenic C57BL/6J background, and increased GFAP staining of astrocytes is found in the pons but to a lesser degree on this mixed genetic background than in homozygotes on the congenic C57BL/6J background
• Background Sensitivity: sciatic nerves from longer-lived homozygotes on this mixed genetic background show a greater degree of swelling than those on the congenic C57BL/6J background, loss of discrete fasicules, increased cellularity of lipid-filled cells, and demyelination
• Background Sensitivity: focal areas of demyelination are found in the cerebellar white matter at the moribund stage, but this is less severe than the extensive demyelination of the cerebellar white matter found in homozygotes on a C57BL/6J congenic background at the moribund stage
• Background Sensitivity: found in the axonal plexus of the granular layer and the cerebellar white matter, but generally not seen in the moribund homozygotes on the C57BL/6J congenic background which die at an earlier age


Mouse Genome Informatics
hm5
    Galctwi/Galctwi
involves: C57BL/6J * CE/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• affected mice live only about 3 months

behavior/neurological

growth/size

hematopoietic system
• multinucleated macrophages contain a variety of abnormal inclusions

immune system
• multinucleated macrophages contain a variety of abnormal inclusions

muscle

nervous system
• degeneration in both central and peripheral nervous systems


Mouse Genome Informatics
hm6
    Galctwi/Galctwi
involves: CE/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• at 40 days of age 10% of oligodendrocytes stain TUNEL positive and there is a correspondence between TUNEL staining and stage of demyelination with the oligodendrocytes with cytoplasmic swelling or thick cellular processes still negative for TUNEL stain and oligodendrocytes with thin or shrunken processes and relatively small soma positive for TUNEL stain
• at 15 days of age the only difference found in the cerebral cortex and corpus callosum is rare cells with focal swelling of the cell soma, but by 20 days of age the oligodendrocytes, identified as expressing glutathione S-transferase pi, display irregular, often polygonal swelling of the cell soma, with or without unstained vacuoles, and with thicker processes and some focal swelling, and after 25 days of age the oligodendrocyte cellular processes and soma become progressively shrunken with only markedly shrunken soma, which lack identifiable processes
• there is gradual decrease in oligodendrocyte number after 35 days of age and very few remain in the cortical layers at 45 days of age

cellular
• at 40 days of age 10% of oligodendrocytes stain TUNEL positive and there is a correspondence between TUNEL staining and stage of demyelination with the oligodendrocytes with cytoplasmic swelling or thick cellular processes still negative for TUNEL stain and oligodendrocytes with thin or shrunken processes and relatively small soma positive for TUNEL stain

homeostasis/metabolism
• 50 times the normal amount of galactosylceramide is found in the kidneys of homozygous mice at 42 days of age with less significant increases in liver and lung
• no abnormal increases of galactosylceramide or sulfatide are noted in the spinal cord or sciatic nerve at any age

renal/urinary system
N
• light microscopy reveals no abnormalities in kidneys of 5 to 45 day old homozygous mice (J:7313)
• light microscopy reveals no abnormalities in kidneys of 5 to 45 day old homozygous mice
• ultrastructural analysis shows increasing amounts of epithelial cell inclusions as mutant mice age
• cytoplasmic inclusions are found in the thin limbs of the loop of Henle in developing papillae of 5 day old mice
• ultrastructural analysis reveals an increasing amount of cytoplasmic inclusions as mice age
• inclusions are restricted to the thin limbs of the loop of Henle but occasionally are seen in the lumen of thta structure
• demonstrated by the occurrence of cytoplsmic inclusions in kidney tissue


Mouse Genome Informatics
ht7
    Galctwi/Galctwi-3J
involves: C57BL/6J * CE/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological

growth/size


Mouse Genome Informatics
cx8
    Galctwi/Galctwi
Ptgdrtm1Sna/Ptgdrtm1Sna

B6.Cg-Galctwi Ptgdrtm1Sna
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• lifespan of mutants is 46.2 days

behavior/neurological
• milder than in Galctwi single mutants

nervous system
• astrocyte processes are much thinner than in Galctwi single mutants


Mouse Genome Informatics
cx9
    Galctwi/Galctwi
Hpgdstm1Urad/Hpgdstm1Urad

B6.Cg-Hpgdstm1Urad Galctwi
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• lifespan of mutants is 47.3 days

cellular
• fewer apoptotic oligodendrocytes are detected in double mutants compared to Galctwi single mutants

behavior/neurological
• milder than in Galctwi single mutants

nervous system
• astrocyte processes are much thinner than in Galctwi single mutants


Mouse Genome Informatics
cx10
    Galctwi/Galctwi
Glb1tm1Azzo/Glb1tm1Azzo

involves: 129P2/OlaHsd * C57BL/6J * CE/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• average lifespan is 74.3 days with some surviving up to 94 days, a significant extension of longevity compared with mice homozygous for twitcher only

hematopoietic system
• macrophage infiltration in the lymph follicles of the spleen at 94 days of age

immune system
• macrophage infiltration in the lymph follicles of the spleen at 94 days of age

liver/biliary system
• at 94 days of age macrophage-filled sinusoids compress the hapatocytes and the hepatic architecture is disrupted

renal/urinary system
• finely vacuolated cells, which stain PAS-negative, are found within the Bowman capsule in the glomeruli
• renal tubular epithelium is diffusely vacuolated

nervous system
• unlike mice homozygous for only the twitcher mutation, the central nervous system shows normal myelination with rare infiltration of globoid cells at 35-40 days of age but progressively more common at 77 and 94 days of age and the sciatic nerve pathology at 94 days of age is similar to that of 35 to 40 day old twitcher controls
• although the central nervous system maintains myelination, the peripheral nervous system shows distinct demyelination

homeostasis/metabolism
• massive lactosylceramide accumulation in brain, kidney, and liver due to a block in lactosylceramide degradation, a reduction to 50-60% of normal levles of galactosylceramide in the kidney and brain, and drastic reduction of brain psychosine levels


Mouse Genome Informatics
cx11
    Galctwi/Galctwi
Glb1tm1Azzo/Glb1+

involves: 129P2/OlaHsd * C57BL/6J * CE/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• average lifespan is 37.7 days and nearly all die before 46 days of age

behavior/neurological
• between 30 and 35 days of age mice are extremely hyper-responsive in response to touching the cage or lifting the lid
• between 30 and 35 days of age the hyper-reactivity can include generalized seizures

nervous system
• between 30 and 35 days of age the hyper-reactivity can include generalized seizures
• at 27 days of age many dying neurons with deeply eosinophilic cytoplasm and pyknotic nuclei are present diffusely in the cerebral cortex where activated astrocytes and microglia/macrophages are found
• neuronal degeneration of the hippocampus is most pronounced in CA3 and the subiculum and scattered necrotic cells are also found in the hypothalamus, amygdala, caudate/putamen and lateral septal nuclei
• cerebral cortex and to a lesser extent the white matter have activated astrocytes and microglia/macrophages with many dying cells present

immune system
N
• spleen is free of pathology (J:63197)

liver/biliary system
N
• liver is free of pathology (J:63197)

homeostasis/metabolism
• at 30 and 40 days of age psychosine is significantly elevated in the brain


Mouse Genome Informatics
cx12
    Galctwi/Galctwi
Il6tm1Kopf/Il6tm1Kopf

involves: 129S2/SvPas * C57BL/6J * CE/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• the average onset of twitching is earlier in double homozygotes than mice homozygous only for twitcher (22.2 days of age versus 25.9 days of age respectively), although lifespan, body weight and frequency of twitching do not differ significantly

nervous system
• leakage of the blood-brain barrier is detected in the cerebrum, hindbrain, and cervical spinal cord as detected by horseradish peroxidase tail vein injection, and immunoglobulin and albumin immunohistochemistry
• lipopolysaccharide injection greatly enhances the blood-brain barrier disruption leading to death
• the deep cerebellar white matter shows a significant increase in periodic acid-Schiff staining cells and a trend toward increased lectin-positive cells relative to mice homozygous only for twitcher
• more exaggerated gliosis is found around some vessels and pial surfaces in the double mutants than in mice homozygous only for twitcher

cardiovascular system
• leakage of the blood-brain barrier is detected in the cerebrum, hindbrain, and cervical spinal cord as detected by horseradish peroxidase tail vein injection, and immunoglobulin and albumin immunohistochemistry
• lipopolysaccharide injection greatly enhances the blood-brain barrier disruption leading to death

homeostasis/metabolism
• hindbrain has TNF levels elevated above that found in mice homozygous only for twitcher and mice homozygous only for twitcher have significantly elevated TNF levels in hindbrain

immune system
• hindbrain has TNF levels elevated above that found in mice homozygous only for twitcher and mice homozygous only for twitcher have significantly elevated TNF levels in hindbrain


Mouse Genome Informatics
cx13
    Galctwi/Galctwi
Il6+/?

involves: 129S2/SvPas * C57BL/6J * CE/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• Background Sensitivity: average lifespan is 39.29 days

cardiovascular system
• modest disruption of the blood-brain barrier detected by immunohistochemical detection of IgG or albumin
• lipopolysaccharide injection results in increased blood-brain barrier disruption and further shortens lifespan

homeostasis/metabolism
• hindbrain has elevated TNF levels (9.38 pg/mg versus 6.54 pg/mg)

immune system
• hindbrain has elevated TNF levels (9.38 pg/mg versus 6.54 pg/mg)

nervous system
• modest disruption of the blood-brain barrier detected by immunohistochemical detection of IgG or albumin
• lipopolysaccharide injection results in increased blood-brain barrier disruption and further shortens lifespan
• the deep cerebellar white matter has periodic acid-Schiff staining globoid cells and lectin-positive macrophages
• severe gliosis in both gray and white matter regions
• most severe in the hindbrain/cervical spinal cord

behavior/neurological
• the average onset of twitching is 25.85 days


Mouse Genome Informatics
cx14
    Csf1op/Csf1op
Galctwi/Galctwi

involves: C3HeB/Fe * C57BL/6J * CE/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mutants have a shorter lifespan than single homozygous Galctwi mice, with a more exacerbated neurological phenotype

behavior/neurological
• mutants develop fine twitching in the neck around P18, 2-3 days earlier than Galctwi mice, and shortly after develop a coarse tremor that gradually spreads from the neck to the trunk
• moribund mice are paralyzed in the hindlimbs

craniofacial

growth/size
• smaller than either single mutant
• mutants start to lose weight between P29 and P33

immune system
• macrophage infiltration in the CNS white matter observed in Galctwi mice is almost completely blocked: although degenerated myelin is observed in the white matter parenchyma, PAS stain is rarely seen, indicating that PAS+ macrophages, or globoid cells are not observed in demyelinated lesions and that there is an absence of myelin phagocytosis by macrophages

nervous system
• white matter exhibits similar reactive astrocytosis as single Galctwi mice, however double mutants have a smaller oligodendrocyte progenitor cell (OPC) population
• levels of psychosine are increased in the forebrain compared to wild-type mice, however levels are lower than in single Galctwi mice, indicating that levels of psychosine do not correlate with the severity of disease
• mutants have lower levels of free sphingosine compared to wild-type mice, and levels are lower in double mutants than in single Galctwi mice
• oligodendrocyte progenitor cells become hypertrophic and have short and stout processes instead of well branched fine processes as in wild-type mice
• mutants exhibit fewer oligodendrocytes than wild-type or single Galctwi mice
• recruitment of oligodendrocyte progenitor cells in response to demyelination is compromised
• mutants exhibit a more severe demyelinating pathology than single homozygous Galctwi mice due to inhibition of remyelination and a delay in myelin development, rather than enhanced demyelination
• myelin degeneration is seen in the white matter, with significantly more nonmyelinated axons at P45 in mutants than single Galctwi mice and a preferential loss of myelin in large diameter axons
• sciatic nerves are severely demyelinated
• however, development (wrapping) of myelin from P15 to P30 is not affected

skeleton

cellular
• macrophage infiltration in the CNS white matter observed in Galctwi mice is almost completely blocked: although degenerated myelin is observed in the white matter parenchyma, PAS stain is rarely seen, indicating that PAS+ macrophages, or globoid cells are not observed in demyelinated lesions and that there is an absence of myelin phagocytosis by macrophages

hematopoietic system
• macrophage infiltration in the CNS white matter observed in Galctwi mice is almost completely blocked: although degenerated myelin is observed in the white matter parenchyma, PAS stain is rarely seen, indicating that PAS+ macrophages, or globoid cells are not observed in demyelinated lesions and that there is an absence of myelin phagocytosis by macrophages