Mouse Genome Informatics
hm1
    Slc4a7tm1Krtz/Slc4a7tm1Krtz
involves: 129S5/SvEvBrd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hearing/vestibular/ear
• at 1 month, homozygotes exhibit a collapsed Reissner membrane
• homozygotes display progressive cochlear hair cell degeneration (J:102942)
• in contrast, hair cells and supporting cells in the vestibular periphery as well as cells within the crista and utricle stroma remain normal from P2 tp P90 (J:102942)
• at 1 month, homozygotes exhibit progressive IHC degeneration that becomes severe by 3 months (J:86635)
• at P21, homozygotes display IHC degeneration in the basal cochlear region, not evident at P15 (J:102942)
• by P30 and P90, homozygotes show complete loss of IHCs in the hook region (J:102942)
• at 1 month, homozygotes exhibit progressive OHC degeneration that becomes severe by 3 months (J:86635)
• by P30 and P90, homozygotes show complete loss of OHCs in the hook region (J:102942)
• at P21, homozygotes display OHC degeneration in the basal cochlear region, not evident at P15 (J:102942)
• at P21, Claudius cells appear damaged
• at P21, homozygotes display degeneration of supporting cells in the basal cochlear region, not evident at P15
• by P30, homozygotes show a marked loss of supporting cells in the organ of Corti
• at 1 month, homozygotes display morphological changes in the spiral ligament
• starting at P21, homozygotes show a progressive loss of type II and IV spiral ligament fibrocytes in the basal to hook regions of the cochlea
• however, no fibrocyte loss is noted in the mid-apical cochlear region at all stages
• notably, type III fibrocytes appear morphologically normal at P30 and P90
• at P30 and P90, type I fibrocytes display clear spaces in the extracellular matrix
• at P30 and P90, homozygotes show a significant loss of type II fibrocytes in the basal to hook regions; less pronounced at P21
• at P30 and P90, type II fibrocytes show cytoplasmic vacuolization and a certain degree of cellular shrinkage
• at P30 and P90, homozygotes show a significant loss of type IV fibrocytes in the basal to hook regions; less pronounced at P21
• at P30 and P90, type IV fibrocytes exhibit cellular shrinkage
• at 1 month, homozygotes display morphological changes in the stria vascularis
• at 1 month, homozygotes show degenerative changes in the basal cochlear region while the mid and apical regions appear unaffected
• at P15, homozygotes show a mild degeneration of the organ of Corti in the basal cochlear region; not evident at P8
• at P21, the organ of Corti is atrophic in the hook region; however, midbasal to apical cochlear region, stria vascularis, Reissner's membrane and spiral ligament remain normal
• by 3 months, homozygotes show significantly lower ABR amplitudes relative to wild-type mice
• homozygotes exhibit increased ABR thresholds above 2 kHz; a threshold difference of 20 dB is detected at 32 kHz, indicating a mild auditory impairment
• however, no major vestibular or motor abnormalities are noted at 1-12 months of age during rotarod and tilt-table expts

vision/eye
• at 2.5 months, homozygotes exhibit apoptotic nuclei in retinal photoreceptors
• at 4 months, homozygotes exhibit abnormal fundus morphology, with blood vessel attenuation and diffuse granularity as observed in retinitis pigmentosa; not evident at 1 month of age
• at 4 months, homozygotes exhibit blood vessel attenuation in the fundus
• at 2 months, homozygotes contain a reduced number of photoreceptor cell nuclei in the outer nuclear layer (ONL); the inner retina remains unaffected
• by 11 months, the superior retina is almost devoid of photoreceptor cells
• only a few scattered nuclei are detected at 14 months
• by 11 months, photoreceptor outer segments are lost and nerve cell process of inner retinal neurons abut the tips of RPE microvilli
• at 2 months, homozygotes display shorter photoreceptor outer segments
• homozygotes exhibit slow photoreceptor death that is nearly complete by 1 year of age
• at 2 months, homozygotes display a ~25% reduction in ONL thickness
• at 6 months, homozygotes show a ~75% reduction in superior ONL thickness and a ~60% reduction in inferior ONL thickness
• at 14 months, the inferior retina is only ~35% of wild-type thickness
• rod-mediated ERGs indicate loss of Vmax (the maximum saturated b-wave amplitude) and an elevation of k (the semi-saturation intensity) with increasing age
• by ~12 months, the Vmax amplitude is less than 10% of the value noted at 1 month while k is more than doubled
• however, at 2.5 months, rod sensitivity to light is unaffected in surviving photoreceptors, suggesting that Ca2+ homeostasis in the outer segment is normal
• homozygotes are viable and fertile with no significant changes in development, behavior, kidney and epididymis morphology and serum or urine electrolyte composition
• however, homozygotes develop blindness due to progressive degeneration of retinal photoreceptors

nervous system
• homozygotes display progressive cochlear hair cell degeneration (J:102942)
• in contrast, hair cells and supporting cells in the vestibular periphery as well as cells within the crista and utricle stroma remain normal from P2 tp P90 (J:102942)
• at 1 month, homozygotes exhibit progressive IHC degeneration that becomes severe by 3 months (J:86635)
• at P21, homozygotes display IHC degeneration in the basal cochlear region, not evident at P15 (J:102942)
• by P30 and P90, homozygotes show complete loss of IHCs in the hook region (J:102942)
• at 1 month, homozygotes exhibit progressive OHC degeneration that becomes severe by 3 months (J:86635)
• at P21, homozygotes display OHC degeneration in the basal cochlear region, not evident at P15 (J:102942)
• by P30 and P90, homozygotes show complete loss of OHCs in the hook region (J:102942)
• at 2 months, homozygotes contain a reduced number of photoreceptor cell nuclei in the outer nuclear layer (ONL); the inner retina remains unaffected
• by 11 months, the superior retina is almost devoid of photoreceptor cells
• only a few scattered nuclei are detected at 14 months
• by 11 months, photoreceptor outer segments are lost and nerve cell process of inner retinal neurons abut the tips of RPE microvilli
• at 2 months, homozygotes display shorter photoreceptor outer segments
• homozygotes exhibit slow photoreceptor death that is nearly complete by 1 year of age
• by 3 months, homozygotes display a moderate loss of spiral ganglion neurons (J:86635)
• by P30 and P90, homozygotes show complete loss of spiral ganglion neurons in the hook region (J:102942)
• degeneration of myelin surrounding the spiral ganglion neurons is noted at P30 and P90 (J:102942)
• cytoplasmic vacuolation of spiral gnaglian neurons is noted at P90 (J:102942)
• in contrast, vestibular ganglion neurons and their fibers remain normal at all stages (J:102942)

cardiovascular system
• at 4 months, homozygotes exhibit blood vessel attenuation in the fundus

skeleton
• at 1 month, homozygotes display morphological changes in the spiral ligament
• starting at P21, homozygotes show a progressive loss of type II and IV spiral ligament fibrocytes in the basal to hook regions of the cochlea
• however, no fibrocyte loss is noted in the mid-apical cochlear region at all stages
• notably, type III fibrocytes appear morphologically normal at P30 and P90
• at P30 and P90, type I fibrocytes display clear spaces in the extracellular matrix
• at P30 and P90, homozygotes show a significant loss of type II fibrocytes in the basal to hook regions; less pronounced at P21
• at P30 and P90, type II fibrocytes show cytoplasmic vacuolization and a certain degree of cellular shrinkage
• at P30 and P90, homozygotes show a significant loss of type IV fibrocytes in the basal to hook regions; less pronounced at P21
• at P30 and P90, type IV fibrocytes exhibit cellular shrinkage

cellular
• at 2.5 months, homozygotes exhibit apoptotic nuclei in retinal photoreceptors

Mouse Models of Human Disease
OMIM IDRef(s)
Usher Syndrome, Type IIC; USH2C 605472 J:86635