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

Abstract

Two mouse models, the Coch G88E/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 Coch G88E/G88E mouse models. Both Coch −/− and Coch G88E/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 Coch G88E/G88E mice have absent ABRs. Interestingly Coch −/+ mice do not show hearing deficits, in contrast to Coch G88E/+ , 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 Coch G88E/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.

A novel COCH mutation associated with autosomal dominant nonsyndromic hearing loss disrupts the structural stability of the vWFA2 domain

“…Based on these results, we hypothesize that the p.F527C mutation of cochlin causes DFNA9 phenotype through cochlin aggregation, rather than through loss of function of the protein. This model implies that the p.F527C mutant cochlin has dominant-negative effects on the hearing functionality of DFNA9 patients and is consistent with the inheritance pattern of our DFNA9 pedigree with this mutation and with the finding of hearing loss in Coch G88E/+ heterozygotes and not in Coch -/+ heterozygotes, reflecting that the mutation’s deleterious effects are likely not the result of haploinsufficiency [25]. …”

Cochlin expression in vestibular endorgans obtained from patients with Meniere’s disease

“…The role of cochlin and the etiology of DFNA9 has been recently studied using a cochlin a knock-out (Coch −/− ) and a knock-in (Coch +/+ ) mouse model (Jones et al 2011). Both mouse models showed elevated auditory brain responses (ABRs) at 21 moths of age.…”

Histopathology of the Human Inner Ear in the p.L114P <b><i>COCH</i></b> Mutation (DFNA9)

“…The von Willebrand domains have been suggested as playing a role in increased shear induced platelet aggregation [Bhattacharya 2006], possibly resulting in vascular disease and secondarily to degenerative disease. The pathogenic genetic mechanism underlying aggregates of mutated cochlin is thought to represent a “gain of function” rather than COCH haploinsufficiency [Makishima et al 2005, Robertson et al 2006, Jones et al 2011]. …”