Mouse Genome Informatics
hm1
    Psaptm1Suz/Psaptm1Suz
B6.129P2-Psaptm1Suz
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• with continued backcrossing to C57BL/6J, most homozygous embryos die in utero; live births are rare

homeostasis/metabolism
N
• galactosylalkylacylglycerol (GalEAG) levels in the testis dramatically increase by 12 days of age, peak at 16 days and decrease rapidly to adult level, similar to pattern of wild-type (J:120657)
• testis contain 150% of normal level of seminolipid at terminal stage of 34 days
• sphingomyelin levels are ~170% of control levels at terminal stage (34 days)

reproductive system
N
• testis weight of homozygotes is not decreased, even at terminal stage of 34 days (J:120657)
• no obvious sign of abnormal spermatogenesis is observed at 30 days (J:120657)


Mouse Genome Informatics
hm2
    Psaptm1Suz/Psaptm1Suz
involves: 129P2/OlaHsd
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• 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
• 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
• a number of homozygotes appear to die in utero

growth/size
• 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
• mice are smaller than littermates at birth and by day 30, body weight is >50% of wild-type or heterozygotes
• after birth mice gain less body weight than littermates

reproductive system
• tubular diameter is smaller than wild-type (J:106511)
• at 25 and 30 days after birth, prostates of mutants are less developed and lined by an epithelium composed of short cells (J:106511)
• prostatic epithelial cells in 37-day old males are shorter than those seen in controls (J:106511)
• reduced in weight by 60% (J:106511)
• glands have smaller tubular diameters and shorter undifferentiated epithelial cells (J:106511)
• seminal vesicles are reduced in weight by 75% (J:106511)
• testes are reduced in weight and size by 30% relative to wild-type controls (J:106511)
• 37-day old males have a reduced number of late spermatids compared to wild-type and heterozygotes (J:106511)
• smaller tubular diameters and shorter undifferentiated epithelial cells are observed in epididymes (J:106511)
• 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 (J:106511)
• reduced in weight by 37% (J:106511)

nervous system
• mice start to show seizure activity around postnatal day 30 (P30)
• at >P30, intermittent seizures develop and progress to continual tonic status epilepticus
• 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
• 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
• choroid plexus epithelial cells contain inclusions detected at P10
• the mutant white matter is pale and ill-defined from the grey matter, suggesting paucity of myelin
• 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
• 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
• 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
• 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
• large inclusions consisting of granular or lamellar structures of various sizes and shapes are detected in many CNS neurons after P30
• at P1, many neurons of DRG contain ubiquitin-positive granular inclusions, similar to the inclusions found in CNS and trigeminal ganglion of older mice
• 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
• 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
• 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

behavior/neurological
• food intake decreases after 30 days of age, coincident with development of neurological symptoms
• 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)
• at ~P18-P20, homozygotes display weakness/ataxia of the hindlegs
• after postnatal day 20 (P20), mice show progressive hindlimb weakness
• majority of mice display seizure-like hyperactivity after P30
• around postnatal day 20 (P20), mice begin to exhibit reduced activity
• around postnatal day 20 (P20), mice develop gait disturbances
• at ~P18-P20, homozygotes display tremulousness of the head
• by P28-P30, homozygotes exhibit gross shaking of the head
• hindlimb paralysis progresses slowly
• mice start to show seizure activity around postnatal day 30 (P30)
• at >P30, intermittent seizures develop and progress to continual tonic status epilepticus

muscle
• some fibers show membranous inclusions
• majority of hindlimb girdle muscles become atrophic around P20
• skeletal muscles show occasional atrophic fibers on P36
• by P30, homozygotes display severe weakness of all legs

renal/urinary system
• affected homozygotes display a significant reduction in kidney size
• no visceral organ abnormalities or organomegaly are observed
• general weight reduction of 19%
• 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

homeostasis/metabolism
• levels are normal or higher in mutants relative to wild-type mice
• 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
• at 40 days, brain levels of psychosine (galactosylsphingosine) is much lower (17.2 pmoL/mg) than in wild-type controls (34 pmol/mg)

endocrine/exocrine glands
• tubular diameter is smaller than wild-type (J:106511)
• at 25 and 30 days after birth, prostates of mutants are less developed and lined by an epithelium composed of short cells (J:106511)
• prostatic epithelial cells in 37-day old males are shorter than those seen in controls (J:106511)
• reduced in weight by 60% (J:106511)
• glands have smaller tubular diameters and shorter undifferentiated epithelial cells (J:106511)
• seminal vesicles are reduced in weight by 75% (J:106511)
• testes are reduced in weight and size by 30% relative to wild-type controls (J:106511)

hematopoietic system
• 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
• general weight reduction of 17%

immune system
• 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
• general weight reduction of 17%

liver/biliary system
• some hepatocytes have lamellar and vesicular inclusions from P10
• general weight reduction of 20%

cardiovascular system
• 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

vision/eye
• neuronal inclusions in ganglion cells increase after P10
• fibroblasts in corneal stroma show inclusions made up of granular and membranous structures at P36


Mouse Genome Informatics
hm3
    Psaptm1Suz/Psaptm1Suz
involves: 129P2/OlaHsd * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• myelin basic protein is decrease to about 45% of normal


Mouse Genome Informatics
hm4
    Psaptm1Suz/Psaptm1Suz
involves: 129P2/OlaHsd * FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hearing/vestibular/ear
• starting at P15 and increasing through P30, homozygotes display a marked hyperplasia of cells surrounding the IHC and in the region of the inner sulcus and greater epithelial ridge
• other structures of the inner ear, including Reisner's membrane, stria vascularis, spiral ganglion, and cochlear scalae, appear unaffected
• starting at P15 and increasing through P30, homozygotes show a small bulge of tissue in the tunnel of Corti adjacent to the inner pillar cell
• as early as P12, homozygotes display a cellular hypertrophy in the region of IHCs, which continues through P30
• NF-200 (afferent auditory neuronal) staining indicates an initial delay in the development of afferent terminals at P11, with subsequent prolific sprouting corresponding to the hypercellular region surrounding the IHC by P21
• at P11, a slightly decreased synaptophysin (efferent auditory neuronal) staining intensity is noted in the region of IHCs
• synaptophysin (efferent auditory neuronal) staining indicates that the tissue bulging into the tunnel of Corti represents a proliferation of efferent nerve terminal endings attempting to cross the tunnel of Corti on their way to OHCs; limited staining is noted in the region of OHCs at both P11 and P21
• starting at P12, homozygotes show up to a 40% loss of OHCs in the cochlear apex extending through the first 2 mm of the cochlear duct, as well as vacuolization of OHCs
• in contrast, IHC numbers remain normal throughout the cochlea
• at >P25, homozygotes display hypertrophy of DCs, with an ill-defined border between DCs and the OHCs relative to wild-type mice
• the synaptic cleft between the OHC and DCs is also abnormally enlarged
• no adequate whole-cell voltage-clamp recordings can be obtained from homozygous mutant OHCs; when achieved, large leak currents are found, and active membrane currents are poor or absent, precluding assessment of cholinergic function
• in contrast, IHC recordings from homozygous mutant mice exhibit normal current-voltage I-V curves both at P7-P11 and at ~3 weeks of age (P19), as well as normal responses to applied acetylcholine, indicating functionally normal cholinergic efferent synapses at the IHC
• at ~2-4 weeks, homozygotes display significantly higher ABR thresholds in response to click stimuli and tone pips at 8, 16, and 32 kHz relative to heterozygous and wild-type littermates
• prior to P19, homozygotes display significantly reduced DPOAE amplitudes at very low (8 kHz) and high (32 kHz) frequencies relative to heterozygous and wild-type mice
• by P30, DPOAEs are significantly reduced at all test frequencies
• homozygotes are deaf by P25
• although auditory development is normal through P19, hearing of homozygotes declines rapidly thereafter

nervous system
• as early as P12, homozygotes display a cellular hypertrophy in the region of IHCs, which continues through P30
• NF-200 (afferent auditory neuronal) staining indicates an initial delay in the development of afferent terminals at P11, with subsequent prolific sprouting corresponding to the hypercellular region surrounding the IHC by P21
• at P11, a slightly decreased synaptophysin (efferent auditory neuronal) staining intensity is noted in the region of IHCs
• synaptophysin (efferent auditory neuronal) staining indicates that the tissue bulging into the tunnel of Corti represents a proliferation of efferent nerve terminal endings attempting to cross the tunnel of Corti on their way to OHCs; limited staining is noted in the region of OHCs at both P11 and P21
• starting at P12, homozygotes show up to a 40% loss of OHCs in the cochlear apex extending through the first 2 mm of the cochlear duct, as well as vacuolization of OHCs
• in contrast, IHC numbers remain normal throughout the cochlea
• no adequate whole-cell voltage-clamp recordings can be obtained from homozygous mutant OHCs; when achieved, large leak currents are found, and active membrane currents are poor or absent, precluding assessment of cholinergic function
• in contrast, IHC recordings from homozygous mutant mice exhibit normal current-voltage I-V curves both at P7-P11 and at ~3 weeks of age (P19), as well as normal responses to applied acetylcholine, indicating functionally normal cholinergic efferent synapses at the IHC


Mouse Genome Informatics
ht5
    Psaptm1Suz/Psap+
involves: 129P2/OlaHsd * FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hearing/vestibular/ear
• at P12-P30, heterozygotes display a subtle cellular hyperplasia of the cells lining the region of the inner sulcus and greater epithelial ridge relative to wild-type mice
• however, overall cochlear morphology and bony anatomy is normal, and no hearing impairment is noted after P19


Mouse Genome Informatics
cx6
    Gbatm2Ggb/Gbatm2Ggb
Psaptm1Suz/Psaptm1Suz

involves: 129P2/OlaHsd * 129S5/SvEvBrd
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• degenerating neurons are seen in multiple brain regions in 12 week old mutants, including the substantia nigra and cortex as indicated by the presence of eosinophilic spheroids
• degenerative changes occur concomitantly with an accumulation of soluble and insoluble alpha-synuclein