Hearing and vestibular deficits in the Coch−/− null mouse model: Comparison to the CochG88E/G88E mouse and to DFNA9 hearing and balance disorder

Two mouse models, the CochG88E/G88E or “knock-in” and the Coch−/− or “knock-out” (Coch null), have been developed to study the human late-onset, progressive, sensorineural hearing loss and vestibular dysfunction known as DFNA9. This disorder results from missense and in-frame deletion mutations in COCH (coagulation factor C homology), encoding cochlin, the most abundantly detected protein in the inner ear. We have performed hearing and vestibular analyses by auditory brainstem response (ABR) and vestibular evoked potential (VsEP) testing of the Coch−/− and CochG88E/G88E mouse models. Both Coch−/− and CochG88E/G88E mice show substantially elevated ABRs at 21 months of age, but only at the highest frequency tested for the former and all frequencies for the latter. At 21 months, 9 of 11 Coch−/− mice and 4 of 8 CochG88E/G88E mice have absent ABRs. Interestingly Coch−/+ mice do not show hearing deficits, in contrast to CochG88E/+, which demonstrate elevated ABR thresholds similar to homozyotes. These results corroborate the DFNA9 autosomal dominant mode of inheritance, in addition to the observation that haploinsufficiency of Coch does not result in impaired hearing. Vestibular evoked potential (VsEP) thresholds were analyzed using a two factor ANOVA (Age X Genotype). Elevated VsEP thresholds are detected in Coch−/− mice at 13 and 21 months, the two ages tested, and as early as seven months in the CochG88E/G88E mice. These results indicate that in both mouse models, vestibular function is compromised before cochlear function. Analysis and comparison of hearing and vestibular function in these two DFNA9 mouse models, where deficits occur at such an advanced age, provide insight into the pathology of DFNA9 and age-related hearing loss and vestibular dysfunction as well as an opportunity to investigate potential interventional therapies.

Research highlights► Characterization of hearing and vestibular function in the Coch “knock-out” and “knock-in” mouse models. ► Comparison of the two mouse models to each other and correlation to the human hearing and vestibular disorder, DFNA9. ► Study of progression of hearing and vestibular deficits with late-onset. ► Missense mutation vs. null expression of the Coch gene. ► Histological analysis of both mouse models and comparison to human DFNA9 disorder.