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

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 the mouse and have created a Coch^G88E/G88E mouse model for the study of DFNA9 pathogenesis and cochlin function. Vestibular-evoked potential (VsEP) thresholds of Coch^G88E/G88E mice were elevated at all ages tested compared with wild-type littermates. At the oldest ages, two out of eight Coch^G88E/G88E mice had no measurable VsEP. Auditory brainstem response (ABR) thresholds of Coch^G88E/G88E mice were substantially elevated at 21 months but not at younger ages tested. At 21 months, four of eight Coch^G88E/G88E mice had absent ABRs at all frequencies tested and two of three Coch^G88E/+ mice had absent ABRs at three of four frequencies tested. Distortion product otoacoustic emission amplitudes of Coch^G88E/G88E mice were substantially lower than Coch^+/+ mice and absent in the same Coch^G88E/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.