Analysis Tools
mortality/aging
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• after P7, homozygotes show a higher rate of mortality; however, most mutants survive up to 3 weeks of age, permitting examination of retinal physiology after eyelid opening (P13 and P14)
(J:63635)
• the first deaths occur at P8, with 100% mortality at P24
(J:77663)
• most deaths occur at P9-P21
(J:108878)
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behavior/neurological
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• by P10-P12, homozygotes exhibit defects in controlling voluntary movements, posture, and balance; these defects increase in severity over time
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• homozygotes show absence of a Preyer reflex
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• at P12-P18, homozygotes fail to display an auditory startle response at the highest test stimulus (120 dB)
• in contrast, homozygotes startle appropriately to tactile stimuli (e.g. air puffs)
• no circling, head tilting or other signs of the classical shaker/salzer phenotype are observed
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• homozygotes exhibit motor coordination deficits, first apparent at ~2 weeks of age
(J:63635)
• in contrast to wild-type littermates, homozygotes are unable to climb a grid at an 80 angle and fall off
(J:77663)
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• at P8-P10, homozygotes develop a severe motor impairment with difficulties righting themselves
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• by P10-P12, homozygotes exhibit loss of balance and occasionally fall on their side
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• by P10-P12, homozygotes show awkward and jerky movements
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• by P10-P12, homozygotes exhibit defects in posture, with frequent falls and rollovers and reduced ability to regain the upright position
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• homozygotes drag their hindlimbs, indicating paralysis
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growth/size/body
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• after P7, homozygotes are considerably smaller than wild-type littermates
(J:63635)
• by P10-P12, homozygotes are readily identifiable by their smaller size
(J:77663)
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• by P10-P12, homozygotes are readily identifiable by their decreased body weight
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• homozygotes stop gaining body weight by P8-P10
(J:77663)
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hearing/vestibular/ear
| N |
• at P17-P21, the thickness of stria vascularis in the first cochlear turn appears normal, indicating that absence of EP is not due merely to degeneration of intermediate cells
• the tunnel of Corti appears fully developed at the time of electrophysiological measurements (P17-P21)
• at P17-P21, the endolymphatic [K+] in the utricle is not different from that of wild-type mice
• at P17-21, no collapse of the vestibular labyrinth is noted, and the major cells types of the ampulla (hair cells, transitional cells, and dark cells) appear normal
• at P17-P21, the utricular potential (UP) is similar to that observed in wild-type mice
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• from P6 to P18, homozygotes display pathological changes at the apical, medial and basal cochlea
• at P6, only subtle changes are observed, while the organ of Corti remains morphologically normal
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• at P17-P21, a large displacement of the Reissner's membrane is observed in the first cochlear turn
(J:75599)
• at P6, both epithelial layers of Reissner membrane show degenerative changes, with numerous necrotic cells in both the endolymphatic cuboidal epithelium lining the cochlear duct and in the perilymphatic squamous epithelium
(J:108878)
• at P9, Reissner membrane becomes progressively atrophic
(J:108878)
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• by P18, Reissner's membrane is collapsed and nearly aligned onto the stria vascularis
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• at P6, Reissner membrane appears distended while other structures of the cochlear duct appear normal
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• homozygotes show progressive collapse of the scala media compartment
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• at P9, IHCs display signs of degeneration (i.e atrophy, vacuolated cytoplasm); however, no obvious changes are noted at P6
• by P18, IHCs are completely absent
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• at P9, OHCs display signs of degeneration (i.e atrophy, vacuolated cytoplasm); however, no obvious changes are noted at P6
• by P18, OHCs are completely absent
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• at P9 and P18, the stria vascularis is significantly atrophic
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• at P9, the tectorial membrane is swollen and shows disorganization in the direction of fibers
• by P18, the tectorial membrane is markedly swollen and atrophic with an irregular direction of fibers, undulating and crisscrossing
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• at P9, mainly type I hair cells exhibit apoptotic nuclei
• in contrast, type II cells and supporting cells appear normal
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• at P9, the saccular membrane is collapsed
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• at P17-P21, the cochlear endolymphatic [K+] is greatly reduced and the endolymphatic space is partially collapsed
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• at P17-P21, the endocochlear potential (EP) is abolished
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• at P17-P21, homozygotes exhibit an auditory brain stem response threshold >81 dB
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• at P17-P21, hearing is severely compromised as shown by the absence of a Preyer reflex
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vision/eye
| N |
• at P11 and P18-P21, mutant retinas show normal organization with no obvious lamination defects
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• in situ measurements of the input resistance of mutant Muller cells indicate an ~10-fold higher resistance relative to wild-type cells
• the resting membrane potential is significantly depolarized, indicating that Muller cell K+ conductance is significantly reduced
• the slow PIII response of the light-evoked electroretinogram, present in wild-type retinas, is completely absent; this response is also absent in wild-type preparations treated with Ba2+ to block Muller cell K+ channels
• in contrast, the b-wave of the ERG is not eliminated, indicating that the b-wave is not generated by K+ currents flowing through Muller cells
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nervous system
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• at P9, IHCs display signs of degeneration (i.e atrophy, vacuolated cytoplasm); however, no obvious changes are noted at P6
• by P18, IHCs are completely absent
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• by P18, OHCs are completely absent
• at P9, OHCs display signs of degeneration (i.e atrophy, vacuolated cytoplasm); however, no obvious changes are noted at P6
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• at P9, mainly type I hair cells exhibit apoptotic nuclei
• in contrast, type II cells and supporting cells appear normal
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• in vitro, mutant oligodendrocytes do not elaborate membrane sheaths, display a large somatic area and fewer branches, and rarely interact with other cells, indicating morphological immaturity
• in contrast, spinal cord neurons from P0-P12 homozygotes exhibit normal physiological and morphological characteristics
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• at P18, homozygotes show a ~50% loss of spiral ganglia neurons and fibers and surrounding non-neuronal cells
• however, the cytoplasm spiral ganglia neurons and their peripheral processes appear normal at P6 and P9
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• at P9, homozygotes display significant degeneration of vestibular ganglia; some neurons have apoptotic nuclei and neuronal cell bodies are missing in certain areas
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• at P9, the cochlear (VIIIth) nerve bundle is markedly atrophic
• central processes of spiral ganglion neurons degenerate, with severe degeneration in the VIIIth nerve which contains their axons
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• at P9, TUNEL staining in spinal cord indicates specific labeling of small nuclei in the gray matter and in distal areas of the white matter, indicating apoptosis of glial cells
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• homozygotes display numerous round and oval vacuoles of varying sizes in the white matter of the spinal cord
• smaller vacuoles contain membranous elements of unknown origin and abnormal myelin sheaths
• in some cases, dysmyelination is accompanied by axonal degeneration
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• in some cases, hypomyelination or dysmyelination of the spinal cord is accompanied by axonal swellings and degeneration
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• at P9, homozygotes exhibit hypomyelination and massive spongiform vacuolation in spinal cord, primarily affecting the white matter and neuropil with severe axonal pathology
• by P18, vacuolation has progressed in inner areas of the white matter
• other defects, including shrunken motoneuron cell bodies, are observed in some gray matter areas
• at P12, magnetic resonance images show hyperintense lesions throughout the whole spinal cord including brainstem areas; however, the cerebellum, midbrain, and cortical regions appear unaffected
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• in vitro, cultured oligodendrocytes from the developing spinal cord show complete absence of inwardly rectifying K+ currents and a depolarized membrane potential
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homeostasis/metabolism
dehydration
(
J:77663
)
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• by P10-P12, homozygotes are readily identifiable by their dehydrated appearance
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| EAST syndrome | DOID:0060484 |
OMIM:612780 |
J:77663 | |
