Phenotypes associated with this allele

• Allele Symbol: Slc26a4^tm1Egr
• Allele Name: targeted mutation 1, Eric D Green
• Allele ID: MGI:2385787
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Slc26a4^tm1Egr/Slc26a4^tm1Egr	either: (involves: 129S6/SvEvTac) or (involves: 129S6/SvEvTac * Black Swiss)	MGI:2385830
hm2	Slc26a4^tm1Egr/Slc26a4^tm1Egr	involves: 129S6/SvEvTac	MGI:3697081
ht3	Slc26a4^tm1Egr/Slc26a4^+	involves: 129S6/SvEvTac	MGI:3712498
cx4	Slc26a4^tm1Egr/Slc26a4^tm1Egr Slc5a8^tm1.1Boet/Slc5a8^tm1.1Boet	involves: 129S6/SvEvTac * C57BL/6	MGI:3811521

Genotype
MGI:2385830

hm1

• Allelic Composition: Slc26a4^tm1Egr/Slc26a4^tm1Egr
• Genetic Background: either: (involves: 129S6/SvEvTac) or (involves: 129S6/SvEvTac * Black Swiss)

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

behavior/neurological

absent pinna reflex ( J:67072 )

• failed to exhibit a Preyer's reflex to a loud clap

impaired coordination ( J:67072 )

• impairment on a rotarod test

head bobbing ( J:67072 )

• pronounced head bobbing at 3 weeks of age

head tilt ( J:67072 )

• pronounced head tilting at 3 weeks of age

abnormal gait ( J:67072 )

• gait unsteadiness evident upon beginning to walk

circling ( J:67072 )

• profound circling behavior at 3 weeks of age

hearing/vestibular/ear

abnormal inner ear morphology ( J:67072 )

• defects detectable at E15

distended Reissner membrane ( J:67072 )

• bulging due to dilation of scala media observed at P1

dilated cochlea ( J:67072 )

• dilated cochlea observed at E15.5-E16.5

fused inner hair cell stereocilia ( J:67072 )

• in some cases, IHC degeneration is associated with enlarged stereocilia

cochlear inner hair cell degeneration ( J:67072 )

• inner hair cell degeneration starting between P7 and P15, with variation among different cochleas as well as areas of the same cochlea

cochlear outer hair cell degeneration ( J:67072 )

• outer hair cell degeneration starting between P7 and P15, with considerable variation among different cochleas as well as areas of the same cochlea

dilated scala media ( J:67072 )

• dilated scala media at P1

abnormal semicircular canal morphology ( J:67072 )

• some mice develop dilated semicircular canals

utricular macular degeneration ( J:67072 )

vestibular saccular macula degeneration ( J:67072 )

enlarged vestibular saccule ( J:67072 )

• dilated saccule observed at E15.5-E16.5

dilated endolymphatic duct ( J:67072 )

• dilated endolymphatic duct starting at E15

dilated endolymphatic sac ( J:67072 )

• dilated endolymphatic sac starting at E15

abnormal otolithic membrane morphology ( J:67072 )

• destruction of the otoconial membrane

absent otoliths ( J:67072 )

• almost complete absence of otoconia

enlarged otoliths ( J:67072 )

• at P30, occasional presence of giant otoconia, when present

increased or absent threshold for auditory brainstem response ( J:67072 )

• failed to show characteristic waveforms by auditory-evoked brainstem response analyses

deafness ( J:67072 )

• at P28-P42, homozygotes show no characteristic ABR waveforms at intensities up to 100 dB SPL and with all four test stimuli, indicating complete hearing loss

sensorineural hearing loss ( J:67072 )

abnormal vestibular system physiology ( J:67072 )

• ~50% of homozygotes exhibit various signs of vestibular dysfunction, including habitual circling behaviour, head-tilting and head-bobbing and/or an abnormal reaching response

• vestibular dysfunction shows variable expressivity with respect to its presence, features and severity, but not age of onset

nervous system

fused inner hair cell stereocilia ( J:67072 )

• in some cases, IHC degeneration is associated with enlarged stereocilia

cochlear inner hair cell degeneration ( J:67072 )

• inner hair cell degeneration starting between P7 and P15, with variation among different cochleas as well as areas of the same cochlea

cochlear outer hair cell degeneration ( J:67072 )

• outer hair cell degeneration starting between P7 and P15, with considerable variation among different cochleas as well as areas of the same cochlea

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Pendred Syndrome		DOID:0060744	OMIM:274600	J:67072

Genotype
MGI:3697081

hm2

• Allelic Composition: Slc26a4^tm1Egr/Slc26a4^tm1Egr
• Genetic Background: involves: 129S6/SvEvTac

hearing/vestibular/ear

distended Reissner membrane ( J:101834 )

• large bulging of Reissner's membrane

dilated cochlea ( J:116301 )

• adult homozygotes exhibit a dilated cochlea, despite normal postnatal cochlear development and the presence of a well-formed tunnel of Corti

cochlear hair cell degeneration ( J:101834 )

organ of Corti degeneration ( J:101834 , J:116301 )

• at ~6 weeks, homozygotes display severe degeneration of the organ of Corti (J:116301)

type I spiral ligament fibrocyte degeneration ( J:101834 )

• apparent loss of type I fibrocytes

type II spiral ligament fibrocyte degeneration ( J:101834 )

• apparent loss of type II fibrocytes

thin spiral ligament ( J:101834 , J:116301 )

• 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)

abnormal strial basal cell morphology ( J:101834 , 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)

abnormal strial intermediate cell morphology ( J:101834 , 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)

abnormal strial marginal cell morphology ( J:101834 , 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)

stria vascularis degeneration ( J:101834 , 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)

thin stria vascularis ( J:116301 )

• at ~6 weeks, homozygotes display a significantly thinned stria vascularis (~2/3 of wild-type thickness)

dilated scala media ( J:101834 )

• enlargement of the scala media

small scala tympani ( J:116301 )

• at ~6 weeks, homozygotes typically exhibit a significantly smaller scala tympani

abnormal spiral limbus morphology ( J:101834 )

• spiral limbus appears flatter than normal

dilated endolymphatic duct ( J:116301 )

• at ~6 weeks, homozygotes show an increased volume of endolymphatic spaces (i.e. severe endolymphatic hydrops)

enlarged otoliths ( J:101834 , J:121448 )

• 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)

abnormal cochlear endolymph ionic homeostasis ( J:121442 )

• 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

absent endocochlear potential ( J:101834 , J:116301 )

• 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)

decreased endocochlear potential ( J:121442 )

• 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

abnormal vestibular endolymph physiology ( J:121448 )

• 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

abnormal vestibular endolymph ionic homeostasis ( J:121448 )

• 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

increased or absent threshold for auditory brainstem response ( J:121442 )

• 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

deafness ( J:121442 )

• homozygotes fail to develop hearing

nonsyndromic hearing loss ( J:67072 )

• at least on a 129Sv/Ev background, homozygotes display non-syndromic deafness with no evidence of thyroid disease

sensorineural hearing loss ( J:116301 )

pigmentation

abnormal strial intermediate cell morphology ( J:101834 , 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)

endocrine/exocrine glands

endocrine/exocrine gland phenotype ( J:67072 , J:139883 )

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)

N • thyroid morphology and function are normal (J:139883)

nervous system

cochlear hair cell degeneration ( J:101834 )

homeostasis/metabolism

abnormal calcium ion homeostasis ( J:121442 , J:121448 )

• 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

head tilt ( J:121448 )

circling ( J:121448 )

skeleton

type I spiral ligament fibrocyte degeneration ( J:101834 )

• apparent loss of type I fibrocytes

type II spiral ligament fibrocyte degeneration ( J:101834 )

• apparent loss of type II fibrocytes

thin spiral ligament ( J:101834 , J:116301 )

• 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		DO ID	OMIM ID(s)	Ref(s)
Pendred Syndrome		DOID:0060744	OMIM:274600	J:101834 , J:116301 , J:121442

Genotype
MGI:3712498

ht3

• Allelic Composition: Slc26a4^tm1Egr/Slc26a4⁺
• Genetic Background: involves: 129S6/SvEvTac

hearing/vestibular/ear

hearing/vestibular/ear phenotype ( J:121442 , J:121448 )

N • heterozygotes begin hearing at P12, as expected, with auditory brain stem response thresholds improving daily and reaching nearly adult levels by P15 (J:121442)

N • at P10, heterozygotes generate an endocochlear potential which grows significantly with further development (as shown at P15 and P35) (J:121442)

N • consistent with this finding, heterozygotes display normal developmental expression of the K⁺ channel Kcnj10 in the stria vascularis (J:121442)

N • at all ages (i.e. both before and after the onset of hearing), the endolymphatic pH of heterozygotes is more alkaline than the perilymphatic pH (J:121442)

N • at P10, Ca²⁺ concentration in endolymph of heterozygotes is lower than Ca²⁺ concentration in perilymph; during further development, endolymphatic Ca²⁺ concentration progressively decreases to adult levels (J:121442)

N • at P30-P142, heterozygotes display normal otoconia, with no significant differences in utricular endolymphatic potential (UP) or in utricular endolymphatic pH and [Ca²⁺] relative to wild-type mice (J:121448)

Genotype
MGI:3811521

cx4

• Allelic Composition: Slc26a4^tm1Egr/Slc26a4^tm1Egr; Slc5a8^tm1.1Boet/Slc5a8^tm1.1Boet
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6

endocrine/exocrine glands

endocrine/exocrine gland phenotype ( J:139883 )

N • thyroid morphology and function are normal