Mouse Genome Informatics
hm
    Slc26a4tm1Egr/Slc26a4tm1Egr
involves: 129S6/SvEvTac
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
hearing/vestibular/ear
• large bulging of Reissner's membrane
• at ~6 weeks, homozygotes display severe degeneration of the organ of Corti (J:116301)
• apparent loss of type I fibrocytes
• apparent loss of type II fibrocytes
• spiral prominence is less prominent and spiral ligament is thinner than normal (J:101834)
• at ~6 weeks, homozygotes show a severe reduction of the spiral ligament in the lateral wall of the cochlea (J:116301)
• however, basal cells at the top and bottom of stria vascularis form tight junctions with surface epithelial cells (J:101834)
• at ~P30, presence of round and oval-shaped openings suggest degeneration of the strial basal cell layer and possible destruction of the basal tight junctional barrier (J:116301)
• between P7 and P15, intermediate cells are present in stria vascularis, but appear hyperpigmented (J:101834)
• at ~P30, homozygotes show signs of degeneration in strial intermediate cells (J:116301)
• marginal cells appear to form a continuous layer, with an aberrant pattern of tight junctions (J:101834)
• at ~P30, marginal cells fail to exhibit a typical cobblestone pattern and show aberrant shapes and sizes (J:116301)
• degeneration of stria vascularis, as evidenced by hyperpigmentation (suggesting unalleviated free radical damage) and an irregular pattern of tight junctions in marginal cells (J:101834)
• at ~P30, homozygotes display signs of stria vascularis degeneration (J:116301)
• at ~6 weeks, homozygotes display a significantly thinned stria vascularis (~2/3 of wild-type thickness)
• enlargement of the scala media
• at ~6 weeks, homozygotes typically exhibit a significantly smaller scala tympani
• spiral limbus appears flatter than normal
• adult homozygotes exhibit a dilated cochlea, despite normal postnatal cochlear development and the presence of a well-formed tunnel of Corti
• at ~6 weeks, homozygotes show an increased volume of endolymphatic spaces (i.e. severe endolymphatic hydrops)
• homozygotes are identified by the presence of one or few very large rhomboedric otoconia in utricular macula (J:101834)
• at P30-P142, homozygotes display a single giant crystal, presumably CaCO3, instead of normal otoconia in the utricle (J:121448)
• at all ages (i.e. both before and after the onset of hearing), the endolymphatic pH of homozygotes is more acidic than the perilymphatic pH
• no difference in the pH of perilymph or blood between wild-type and homozygous mutant mice is observed
• in contrast to heterozygotes, endolymphatic Ca2+ concentration in homozygotes is similar to perilymphatic Ca2+ concentration at P10 and progressively increases during further development
• no difference in the Ca2+ concentration of perilymph or blood between wild-type and homozygous mutant mice is observed
• no significant differences in perilymphatic or plasma K+ concentrations are observed (J:101834)
• loss of endocochlear potential is associated with absence of the KCNJ10 K+ channel in stria vascularis but not in spiral ganglia (J:101834)
• expression of KCNJ10 mRNA is normal in stria vascularis and spiral ganglia of young homozygotes (1-4 months) but significantly reduced in older homozygotes (~12 months) (J:101834)
• at ~6 weeks, homozygotes show near absence of a normal EP in both the basal and apical cochlear turns (J:116301)
• induction of anoxia results in a reduced magnitude of the negative EP value, consistent with a loss of functional hair cells (J:116301)
• notably, cochlear endolymphatic [K+], as well as utricular potential (UP) and utricular endolymphatic [K+] remain normal (J:116301)
• at P10, homozygotes generate a small endocochlear potential which is progressively lost during further development
• consistent with this finding, protein expression of K+ channel Kcnj10 in the stria vascularis is noted at P10 but is progressively lost during further development
• young adult homozygotes (P30-P142) display a small, but statistically significant, reduction of ~3 mV in utricular endolymphatic potential (UP) relative to wild-type mice
• at P30-P142, homozygotes display a significantly lower pH and higher [Ca2+] in utricular endolymph relative to wild-type or heterozygous mice
• in addition, utricular endolymphatic [Ca2+] is significantly increased to a level higher than in perilymph, consistent with the presence of altered otoconia
• however, no significant differences are observed in perilymphatic pH and [Ca2+] relative to control values
• homozygotes lack hearing at all ages tested, as determined by auditory brain stem recordings using click and tone-burst stimuli at 8, 16, and 32 kHz
• homozygotes fail to develop hearing
• at least on a 129Sv/Ev background, homozygotes display non-syndromic deafness with no evidence of thyroid disease

pigmentation
• between P7 and P15, intermediate cells are present in stria vascularis, but appear hyperpigmented (J:101834)
• at ~P30, homozygotes show signs of degeneration in strial intermediate cells (J:116301)

endocrine/exocrine glands
N
• at least a 129Sv/Ev background, homozygotes exhibit no signs of overt hypothyroidism at any age up to 2 years; standard serum thyroid function tests are normal (J:67072)
• thyroid morphology and function are normal (J:139883)

nervous system

homeostasis/metabolism
• endolymphatic acidification causes inhibition of Ca2+ reabsorption from the vestibular endolymph via the acid-sensitive Ca2+ channels Trpv5 and Trpv6; as a result, the endolymphatic Ca2+ concentration is progressively increased (J:121442)
• vestibular dysfunction is partly attributed to a pathological elevation of utricular endolymphatic [Ca2+] due to luminal acidification and consequent inhibition of TRPV5/6-mediated Ca2+ absorption (J:121448)

behavior/neurological

skeleton
• apparent loss of type I fibrocytes
• apparent loss of type II fibrocytes
• spiral prominence is less prominent and spiral ligament is thinner than normal (J:101834)
• at ~6 weeks, homozygotes show a severe reduction of the spiral ligament in the lateral wall of the cochlea (J:116301)

Mouse Models of Human Disease
OMIM IDRef(s)
Pendred Syndrome; PDS 274600 J:101834 , J:116301 , J:121442