A targeted Coch missense mutation: a knock-in mouse model for DFNA9 late-onset hearing loss and vestibular dysfunction

Abstract

Mutations in COCH (coagulation factor C homology) are etiologic for the late-onset, progressive, sensorineural hearing loss and vestibular dysfunction known as DFNA9. We introduced the G88E mutation by gene targeting into themouseand have created aCochG88E/G88Emousemodel for the study ofDFNA9pathogenesis and cochlin function. Vestibular-evoked potential (VsEP) thresholds of CochG88E/G88E mice were elevated at all ages tested compared with wild-type littermates. At the oldest ages, two out of eight CochG88E/G88E mice had no measurable VsEP. Auditory brainstem response (ABR) thresholds of CochG88E/G88E mice were substantially elevated at 21 months but not at younger ages tested. At 21 months, four of eight CochG88E/G88E mice had absent ABRs at all frequencies tested and two of three CochG88E/1 mice had absent ABRs at three of four frequencies tested. Distortion product otoacoustic emission amplitudes of CochG88E/G88E mice were substantially lower than Coch1/1 mice and absent in the same CochG88E/G88E mice with absent ABRs. These results suggest that vestibular function is affected beginning as early as 11 months when cochlear function appears to be normal, and dysfunction increases with age. Hearing loss declines substantially at 21 months of age and progresses to profound hearing loss at some to all frequencies tested. This is the only mouse model developed to date where hearing loss begins at such an advanced age, providing an opportunity to study both progressive age-related hearing loss and possible interventional therapies. Originally published Human Molecular Genetics, Vol. 17, No. 21, Nov 2008