Mature middle and inner ears express Chd7 and exhibit distinctive pathologies in a mouse model of CHARGE syndrome

• Published in: Hearing research Vol. 282; no. 1; pp. 184 - 195
• Main Authors: Hurd, Elizabeth A., Adams, Meredith E., Layman, Wanda S., Swiderski, Donald L., Beyer, Lisa A., Halsey, Karin E., Benson, Jennifer M., Gong, Tzy-Wen, Dolan, David F., Raphael, Yehoash, Martin, Donna M.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.12.2011; Elsevier
• Subjects: Acoustic Stimulation; Age Factors; Animals; Auditory Threshold; beta-Galactosidase - genetics; beta-Galactosidase - metabolism; Biological and medical sciences; CHARGE Syndrome - enzymology; CHARGE Syndrome - genetics; CHARGE Syndrome - pathology; CHARGE Syndrome - physiopathology; Disease Models, Animal; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Ear, auditive nerve, cochleovestibular tract, facial nerve: diseases, semeiology; Ear, Inner - abnormalities; Ear, Inner - enzymology; Ear, Inner - physiopathology; Ear, Inner - ultrastructure; Ear, Middle - abnormalities; Ear, Middle - enzymology; Ear, Middle - physiopathology; Ear, Middle - ultrastructure; Evoked Potentials, Auditory, Brain Stem; Female; Fundamental and applied biological sciences. Psychology; Genes, Reporter; Hearing Loss, Conductive - enzymology; Hearing Loss, Conductive - genetics; Hearing Loss, Conductive - pathology; Hearing Loss, Conductive - physiopathology; Hearing Loss, Sensorineural - enzymology; Hearing Loss, Sensorineural - genetics; Hearing Loss, Sensorineural - pathology; Hearing Loss, Sensorineural - physiopathology; Immunohistochemistry; Male; Medical sciences; Mice; Mice, 129 Strain; Mice, Transgenic; Microscopy, Electron, Scanning; Molecular Motor Proteins - metabolism; Motor control and motor pathways. Reflexes. Control centers of vegetative functions. Vestibular system and equilibration; Mutation; Noise; Non tumoral diseases; Otoacoustic Emissions, Spontaneous; Otorhinolaryngology. Stomatology; Promoter Regions, Genetic; Vertebrates: nervous system and sense organs; ABR; DPOAE; HL; IHC; BAHA; CHD7; SNHL; SEM; dB SPL; OHC; Animal model; Skin disease; Middle ear disease; Electrophysiology; Auditory disorder; Conduction hearing loss; Cardiovascular disease; Prestin; Inner ear; Organ of hearing; Gene; ENT disease; Noise pollution; Vestibular syndrome; Vestibular system; Complex syndrome; Middle ear; Hair; Nervous system diseases; Urinary system disease; Internal ear disease; Rodentia; DNA binding protein; Acoustic trauma; Concomitant disease; Vertebrata; Mammalia; Mouse; Polypathology; Semicircular canal; Cochlea; Inner hair cell; CHARGE syndrome; Mutation
• ISSN: 0378-5955; 1878-5891
• DOI: 10.1016/j.heares.2011.08.005

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. ► Chd7Gt/+ mice, a model of human CHARGE syndrome, have mixed sensorineural and conductive hearing loss. ► This paper reports a detailed examination of auditory structure and function in Chd7 mutant mice. ► Chd7Gt/+ mutant mice exhibit protection from inner ear damage due to noise exposure. ► Chd7 mutant mice have middle ear defects. ► Chd7 is abundantly expressed in the mature cochlea, vestibular sensory epithelium, and developing middle ear.