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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.

Pubmed ID: 18697796

Authors

  • Robertson NG
  • Jones SM
  • Sivakumaran TA
  • Giersch AB
  • Jurado SA
  • Call LM
  • Miller CE
  • Maison SF
  • Liberman MC
  • Morton CC

Journal

Human molecular genetics

Publication Data

November 1, 2008

Associated Grants

  • Agency: NIDCD NIH HHS, Id: DC006443
  • Agency: NIDCD NIH HHS, Id: DC0118
  • Agency: NIDCD NIH HHS, Id: DC03402
  • Agency: NIDCD NIH HHS, Id: P30 DC005209
  • Agency: PHS HHS, Id: P30-05209
  • Agency: NIDCD NIH HHS, Id: R01 DC000188
  • Agency: NIDCD NIH HHS, Id: R01 DC003402
  • Agency: NIDCD NIH HHS, Id: R01 DC006443
  • Agency: NIDCD NIH HHS, Id: R01 DC006443-03

Mesh Terms

  • Animals
  • Cochlear Duct
  • Disease Models, Animal
  • Evoked Potentials, Auditory, Brain Stem
  • Extracellular Matrix Proteins
  • Gene Knock-In Techniques
  • Hearing Loss
  • Mice
  • Mice, Inbred C57BL
  • Mutation, Missense
  • Proteins
  • Vestibular Diseases
  • Vestibular Function Tests