title: Mature middle and inner ears express Chd7 and exhibit distinctive pathologies in a mouse model of CHARGE syndrome.
abstract: 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.
authors.affiliation: Department of Pediatrics, 3520A MSRB I, University of Michigan, Ann Arbor, MI 48109-5652, USA. lizhurd@umich.edu
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Hurd
authors.forename: Meredith E
authors.initials: ME
authors.lastname: Adams
authors.forename: Wanda S
authors.initials: WS
authors.lastname: Layman
authors.forename: Donald L
authors.initials: DL
authors.lastname: Swiderski
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Beyer
authors.forename: Karin E
authors.initials: KE
authors.lastname: Halsey
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Benson
authors.forename: Tzy-Wen
authors.initials: TW
authors.lastname: Gong
authors.forename: David F
authors.initials: DF
authors.lastname: Dolan
authors.forename: Yehoash
authors.initials: Y
authors.lastname: Raphael
authors.forename: Donna M
authors.initials: DM
authors.lastname: Martin
mesh_terms: D000161:Acoustic Stimulation; D000367:Age Factors; D000818:Animals; D001309:Auditory Threshold; D058747:CHARGE Syndrome / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D007758:Ear, Inner / Q000002:abnormalities / Q000201:enzymology* / Q000503:physiopathology / Q000648:ultrastructure; D004432:Ear, Middle / Q000002:abnormalities / Q000201:enzymology* / Q000503:physiopathology / Q000648:ultrastructure; D016057:Evoked Potentials, Auditory, Brain Stem; D005260:Female; D017930:Genes, Reporter; D006314:Hearing Loss, Conductive / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006319:Hearing Loss, Sensorineural / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D008855:Microscopy, Electron, Scanning; D020409:Molecular Motor Proteins / Q000378:metabolism; D009154:Mutation; D009622:Noise; D017084:Otoacoustic Emissions, Spontaneous; D011401:Promoter Regions, Genetic; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: C507367:Chd7 protein, mouse; D004268:DNA-Binding Proteins; D020409:Molecular Motor Proteins; C498720:Pres protein, mouse; D001616:beta-Galactosidase