Mouse Genome Informatics
hm
    Gjb6tm1Kwi/Gjb6tm1Kwi
involves: 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       

Transmission electron microscopy analysis of stria vascularis capillaries in Gjb6tm1Kwi/Gjb6tm1Kwi mice

hearing/vestibular/ear
• 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
• 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
• at 2 months, IHCs are degenerated via apoptosis (J:119517)
• at 2 months, OHCs are completely degenerated via apoptosis (J:119517)
• adult homozygotes exhibit apoptosis and degeneration of the organ of Corti
• 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
• 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
• 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
• the endocochlear potential is virtually undetectable in adulthood
• 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)
• cochlear cultures fail to propagate calcium signals or release ATP following photostimulation with caged IP3 unlike wild-type cultures
• 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)
• homozygotes exhibit severe hearing loss at the onset of hearing and are completely deaf by 2 months of age
• adult homozygotes exhibit aggravation of hearing loss

behavior/neurological
• at 4 months, homozygotes exhibit no Preyer reflex, indicating severe hearing loss

nervous system
• 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
• at 2 months, IHCs are degenerated via apoptosis (J:119517)
• at 2 months, OHCs are completely degenerated via apoptosis (J:119517)
• cochlear cultures fail to propagate calcium signals or release ATP following photostimulation with caged IP3 unlike wild-type cultures

cardiovascular system
• 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

homeostasis/metabolism
• 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

immune system
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 (J:85065)

Mouse Models of Human Disease
OMIM IDRef(s)
Deafness, Autosomal Recessive 1A; DFNB1A 220290 J:80917