Human Molecular Genetics Advance Access published online on August 12, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn236
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A targeted Coch missense mutation: a knock-in mouse model for DFNA9 late-onset hearing loss and vestibular dysfunction
1 Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA 2 Department of Communication Sciences and Disorders, East Carolina University, Greenville, NC, USA 3 Department of Otology and Laryngology, Eaton Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, MA, USA 4 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
* Address correspondence to: Cynthia C. Morton, Ph.D., Departments of Ob/Gyn and Pathology, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, NRB 160, Boston, MA 02115, USA Tel: (617) 525-4535, Fax: (617) 525-4533, Email: cmorton{at}partners.org
Received March 17, 2008; Revised July 26, 2008; Accepted August 6, 2008
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 CochG88E/G88E mouse model for the study of DFNA9 pathogenesis and cochlin function. Vestibular evoked potential (VsEP) thresholds for CochG88E/G88E mice were elevated at all ages tested compared to wild-type littermates. At the oldest ages, 2 out of 8 CochG88E/G88E mice had no measurable VsEP. Auditory brainstem response (ABR) thresholds for CochG88E/G88E mice were substantially elevated at 21 months but not at younger ages tested. At 21 months, 4 of 8 CochG88E/G88E mice had absent ABRs at all frequencies tested and 2 of 3 CochG88E/+ mice had absent ABRs at 3 of 4 frequencies tested. Distortion product otoacoustic emission (DPOAE) amplitudes of CochG88E/G88E mice were substantially lower than Coch+/+ 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.
+ Current address: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106
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