Analysis Tools
hearing/vestibular/ear
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Allele Symbol Allele Name Allele ID |
Gjb6tm1Kwi targeted mutation 1, Klaus Willecke MGI:2447863 |
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| Summary |
5 genotypes
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Transmission electron microscopy analysis of stria vascularis capillaries in Gjb6tm1Kwi/Gjb6tm1Kwi mice
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• homozygotes exhibit disruption of the stria vascularis endothelial barrier prior to the onset of endocochlear potential (EP); this result in an intrastrial electric shunt that is sufficient to account for the failure of EP production
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• cell apoptosis in the sensory epithelium occurs from P18 onward and leads to loss of many hair cells; deterioration varies from one mutant animal to the other and affects all cell types, but mainly affects the outer and inner hair cells
• hair cell degeneration occurs gradually with age: 3-week-old mutants have both intact and degenerated hair cells, whereas 4-month-old animals exhibit more extensive hair cell loss
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• at 2 months, IHCs are degenerated via apoptosis
(J:119517)
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• at 2 months, OHCs are completely degenerated via apoptosis
(J:119517)
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• adult homozygotes exhibit apoptosis and degeneration of the organ of Corti
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• however, at P13 (i.e. prior to the degeneration of the organ of Corti), homozygotes display a normal SV electrogenic machinery, as shown by a normal K+ concentration, normal endolymph volume and immunofluorescence detection of Kcnj10, Kcnq1, and Kcne1 K+ channel subunits and H+/K+ATPase in cochlea lateral wall sections
• at P13, immunofluorescence and functional analyses indicate that the integrity of the SV marginal cell and basal cell tight junction barriers is preserved
• the endothelial barrier of capillaries supplying the SV is selectively disrupted before EP onset, as shown by immunofluorescence detection of serum proteins outside SV capillaries from P10 onward
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• at P13, many SV capillaries are abnormally delimited by multiple layers of endothelial cells rather than the expected single layer
• in addition, the basal lamina is often split into several sheets, and intercellular spaces are enlarged at membrane interfaces, with junctional regions appearing as electron-transparent zones
• however, no such abnormalities are observed in spiral ligament capillaries
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• adult homozygotes show a significant reduction in endolymphatic K+ concentration
• in adultood, low endolymphatic K+ concentration results in further decrease of the transducer current driving force, contributing directly to profound deafness
• however, at an earlier age (P13-P14), before the first cells of the sensory epithelium undergo apoptosis, endolymphatic K+ concentration is normal
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• the endocochlear potential is virtually undetectable in adulthood
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• starting at ~P12, homozygotes display loss of the endocochlear potential
(J:80917)
• at 4 months of age, average EPs measured in wild-type and homozygous mutant mice are 93.6 7.8 and 8.6 2.9, respectively
(J:119517)
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• cochlear cultures fail to propagate calcium signals or release ATP following photostimulation with caged IP3 unlike wild-type cultures
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• young homozygous mutant mice (P17-P18) exhibit detectable, though increased, auditory thresholds
(J:80917)
• by 4 months, adult homozygotes show no detectable response up to 100 dB, indicating severe hearing loss
(J:80917)
• at 3-4 weeks, homozygotes display significantly increased ABR thresholds across a frequency range of 4-32 kHz
(J:119517)
• by 2 months, homozygotes exhibit ABR hearing thresholds of >90 dB at all test frequencies
(J:119517)
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• homozygotes exhibit severe hearing loss at the onset of hearing and are completely deaf by 2 months of age
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• adult homozygotes exhibit aggravation of hearing loss
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• at 4 months, homozygotes exhibit no Preyer reflex, indicating severe hearing loss
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• cell apoptosis in the sensory epithelium occurs from P18 onward and leads to loss of many hair cells; deterioration varies from one mutant animal to the other and affects all cell types, but mainly affects the outer and inner hair cells
• hair cell degeneration occurs gradually with age: 3-week-old mutants have both intact and degenerated hair cells, whereas 4-month-old animals exhibit more extensive hair cell loss
|
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• at 2 months, IHCs are degenerated via apoptosis
(J:119517)
|
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• at 2 months, OHCs are completely degenerated via apoptosis
(J:119517)
|
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• cochlear cultures fail to propagate calcium signals or release ATP following photostimulation with caged IP3 unlike wild-type cultures
|
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• at P13, many SV capillaries are abnormally delimited by multiple layers of endothelial cells rather than the expected single layer
• in addition, the basal lamina is often split into several sheets, and intercellular spaces are enlarged at membrane interfaces, with junctional regions appearing as electron-transparent zones
• however, no such abnormalities are observed in spiral ligament capillaries
|
|
• homozygotes exhibit disruption of the stria vascularis endothelial barrier prior to the onset of endocochlear potential (EP); this result in an intrastrial electric shunt that is sufficient to account for the failure of EP production
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• from P10 onward, transcriptome analysis indicates specific down-regulation of betaine homocysteine S-methyltransferase in the stria vascularis, resulting in a local increase in homocysteine, known to cause endothelial dysfunction
• however, homocysteine metabolism is not altered elsewhere in the cochlea or brain, consistent with evidence of a normal plasma homocysteine level and thiol-redox status
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| N |
• analysis of residual connexin expression and examination of wound healing indicates that homozygotes do not display any obvious abnormalities in normal and wounded tail epidermis relative to wild-type mice
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| autosomal recessive nonsyndromic deafness 1A | DOID:0110475 |
OMIM:220290 |
J:80917 | |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• homozygous mice spend less time in the center and more time in the corners in an open field and cross the center of an open field with higher velocity than wild-type mice
• homozygous mice visit a familiar object displaced to the center of an open field less frequently than wild-type mice
• no difference was detected in a graded anxiety test between homozygous and wild-type mice
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• during open field and object exploration tests homozygous mice spent less time rearing
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| N |
• no gross abnormalities were detected in sections from various brain regions
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• choline levels in the ventral striatum are increased
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• acetylcholine levels in the ventral striatum are reduced and choline levels in the frontal cortex and neostriatal increased compared to wild-type mice
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• dopamine and some dopamine metabolite levels are decreased in the amygdala and ventral striatum compared to wild-type mice
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• mutant mice bearing extra copies of the Gjb2 gene, where Gjb2 protein translation is restored to wild-type levels in the cochlea, exhibit complete rescue of the deafness phenotype observed in Gjb6tm1Kwi homozygotes, as shown by prevention of hair-cell death in the organ of Corti, normal ABR thresholds across a frequency range of 4-32 kHz at 4 weeks and 4 months, and complete recovery of large positive endocochlear potentials in rescued mice
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Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO) |
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last database update 04/16/2024 MGI 6.23 |
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