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 Chd7Gt/+ mice. Hearing thresholds by auditory brainstem response (ABR) testing were elevated at 4 and 16 kHz in Chd7Gt/+ mice, and there were reduced distortion product otoacoustic emissions (DPOAE). Exposure of Chd7Gt/+ 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 Chd7Gt/+ mice have combined conductive and sensorineural hearing loss, correlating with changes in both middle and inner ears.

CHD7 Deficiency in “Looper”, a New Mouse Model of CHARGE Syndrome, Results in Ossicle Malformation, Otosclerosis and Hearing Impairment

“…Furthermore, the severity of Looper hearing loss and ossicle malformation differed from that of published Chd7 mutants on different genetic backgrounds [28], [31]. These observations indicate that modifier genes affect the severity of the Chd7 -deficient hearing phenotype.…”

More Clinical Overlap between 22q11.2 Deletion Syndrome and CHARGE Syndrome than Often Anticipated

“…Randall et al [2009] hypothesised that Chd7 might modulate Tbx1 expression but were unable to prove that the expression of either gene changed in mouse embryos mutated at the other locus. Hurd et al [2011] showed that Tbx1 expression was expanded more ventrally in the develop-G e n e D is e a se C h o a n a l a tr e si a C ra n ia l n e rv e d ys fu n ct io n S e m ic ir cu la r ca n a l a n o m a lie s C o n g e n it a l h e a rt d e fe ct R e n a l a n o m a lie s In te lle ct u a l d is a b ili ty G ro w th d e fi ci e n cy G e n it a l h yp o p la si a P it u it a ry p ro b le m s M ic ro p h th a lm ia /c o lo b o m a E xt e rn a l e a r a n o m a lie s H e a ri n g lo ss C le ft lip a n d /o r p a la te O e so p h a g e a l a tr e si a H yp o ca lc a e m ia Im m u n o d e fi ci e n cy figure 3, we show the overlapping clinical features of CHARGE and 22q11.2 deletion syndrome with known genetic syndromes. All the genes mentioned in this figure or their proteins have been associated with either CHD7 or TBX1.…”

Inner ear manifestations in CHARGE: Abnormalities, treatments, animal models, and progress toward treatments in auditory and vestibular structures

“…Analysis of Chd7 Gt/+ mice uncovered additional new phenotypes including mixed conductive and sensorineural hearing loss, middle ear structural abnormalities, and defects in highly specific regions of the vestibular system including lack of innervation to the posterior crista ampullaris [Adams et al, 2007; Hurd et al, 2011; Hurd et al, 2007]. …”

“…Interestingly, Chd7 was recently shown to regulate granule cells in the cerebellum and stem cells in the hippocampus, raising the possibility that auditory and vestibular neural pathways in the brain may also be sensitive to Chd7 loss [Feng et al, 2017; Feng et al, 2013; Jones et al, 2015; Whittaker et al, 2017]. Use of heterozygous mutant Chd7 mice has also led to the discovery that haploinsufficiency for Chd7 may protect from noise-induced hearing loss, likely related to conductive hearing loss and middle ear structural abnormalities [Hurd et al, 2011]. …”