RESUMEN
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.
Asunto(s)
Pérdida Auditiva/genética , Mutación Missense , Proteínas/genética , Enfermedades Vestibulares/genética , Animales , Conducto Coclear/patología , Modelos Animales de Enfermedad , Potenciales Evocados Auditivos del Tronco Encefálico , Proteínas de la Matriz Extracelular , Técnicas de Sustitución del Gen , Ratones , Ratones Endogámicos C57BL , Pruebas de Función VestibularRESUMEN
The past year has seen major advances in our understanding of the genes involved in Usher syndrome, as well as the discovery of a myriad of other genes expressed specifically in hair cells. Mouse models continue to be invaluable in illuminating our knowledge of how mutations in genes lead to deafness. The role of mitochondrial genes in the hearing process has also contributed to elucidating the workings of the auditory system.
