Heterozygous mutations in the gene encoding chromodomain-DNA-binding-protein 7 (CHD7) cause CHARGE syndrome, a multiple anomaly condition which includes vestibular dysfunction and hearing loss. Mice with heterozygous Chd7 mutations exhibit semicircular canal dysgenesis and abnormal inner ear neurogenesis, and are an excellent model of CHARGE syndrome. Here we characterized Chd7 expression in mature middle and inner ears, analyzed morphological features of mutant ears and tested whether Chd7 mutant mice have altered responses to noise exposure and correlated those responses to inner and middle ear structure. We found that Chd7 is highly expressed in mature inner and outer hair cells, spiral ganglion neurons, vestibular sensory epithelia and middle ear ossicles. There were no obvious defects in individual hair cell morphology by Prestin immunostaining or scanning electron microscopy, and cochlear innervation appeared normal in Chd7 Gt/+ mice. Hearing thresholds by auditory brainstem response (ABR) testing were elevated at 4 and 16 kHz in Chd7 Gt/+ mice, and there were reduced distortion product otoacoustic emissions (DPOAE). Exposure of Chd7 Gt/+ mice to broadband noise resulted in variable degrees of hair cell loss which inversely correlated with severity of stapedial defects. The degrees of hair cell loss and threshold shifts after noise exposure were more severe in wild type mice than in mutants. Together, these data indicate that Chd7 Gt/+ mice have combined conductive and sensorineural hearing loss, correlating with changes in both middle and inner ears.
Bibliographical noteFunding Information:
This work was supported by the Williams Professorship, the A. Alfred Taubman Medical Research Institute and the Berte and Alan Hirschfield Foundation (Y.R), NOHR (D.M.M), and NIH/NIDCD grants P30 DC05188 (Y.R and D.F.D) and R01 DC009410 (D.M.M and Y.R).