Cochlin in Normal Middle Ear and Abnormal Middle Ear Deposits in DFNA9 and Coch G88E/G88E Mice

Abstract

DFNA9 sensorineural hearing loss and vestibular disorder, caused by mutations in COCH, has a unique identifying histopathology including prominent acellular deposits in cochlear and vestibular labyrinths. A recent study has shown presence of deposits also in middle ear structures of DFNA9-affected individuals (McCall et al., J Assoc Res Otolaryngol 12:141-149, 2004). To investigate the possible role of cochlin in the middle ear and in relation to aggregate formation, we evaluated middle ear histopathology in our Coch knock-in (Coch (G88E/G88E) ) mouse model, which harbors one of the DFNA9-causative mutations. Our findings reveal accumulation of acellular deposits in the incudomalleal and incudostapedial joints in Coch (G88E/G88E) mice, similar to those found in human DFNA9-affected temporal bones. Aggregates are absent in negative control Coch (+/+) and Coch (-/-) mice. Thickening of the tympanic membrane (TM) found in humans with DFNA9 was not appreciably detected in Coch (G88E/G88E) mice at the evaluated age. We investigated cochlin localization first in the Coch (+/+)mouse and in normal human middle ears, and found prominent and specific cochlin staining in the incudomalleal joint, incudostapedial joint, and the pars tensa of the TM, which are the three sites where abnormal deposits are detected in DFNA9-affected middle ears. Cochlin immunostaining of Coch (G88E/G88E) and DFNA9-affected middle ears showed mutant cochlin localization within areas of aggregates. Cochlin staining was heterogeneous throughout DFNA9 middle ear deposits, which appear as unorganized and overlapping mixtures of both eosinophilic and basophilic substances. Immunostaining for type II collagen colocalized with cochlin in pars tensa of the tympanic membrane. In contrast, immunostaining for type II collagen did not overlap with cochlin in interossicular joints, where type II collagen was localized in the region of the chondrocytes, but not in the thin layer of the articular surface of the ossicles nor in the eosinophilic deposits with specific cochlin staining.

NovelCOCHp.V123E Mutation, Causative of DFNA9 Sensorineural Hearing Loss and Vestibular Disorder, Shows Impaired Cochlin Post-Translational Cleavage and Secretion

“…This scenario is compatible with the evidence that chronic otitis media causes sensorineural hearing loss driven by inflammatory mediators in response to various endotoxins [Guo et al., ; Morizono et al., ; Paparella et al., , ]. Moreover, a recent study has reported that eosinophilic aggregates colocalized with cochlin staining are present in the middle ear of the p.G88E‐cochlin knock‐in mice [Robertson et al., ]. Cumulatively, these data suggest that cochlin may have an important role in the innate immune response within both middle and inner ear compartments.…”

Cochlin Deficiency Protects Against Noise-Induced Hearing Loss

“…Using a combination of physiological tests that assess cochlear function, here we demonstrate for the first time that Coch −/− mice have a small conductive hearing loss compared to Coch +/+ littermates, and possibly additional sensorineural component at the highest tested frequency. Together with the previously reported expression of cochlin in the murine and human middle ear, precisely on the articular surfaces of the incudomalleal and incudostapedial joints as well as pars tensa of the tympanic membrane (Robertson et al, 2014), we highlight cochlin's importance in sound conduction across the middle ear. In previous studies, a trend for increased ABR thresholds was present in young Coch −/− mice compared to Coch +/+ mice, although this trend did not reach the authors' criterion for significance (Choe et al, 2019).…”

Histopathology of the Human Inner Ear in the p.L114P <b><i>COCH</i></b> Mutation (DFNA9)

“…This is the first description of the histopathology of the inner ear in this specific mutation. The histopathologic findings were similar to those previously described in other kinships (Table 1), both in the inner ear and in the extracochlear locations as previously described [McCall et al 2011; Robertson et al 2014]. Within the cochlea, the histopathologic findings include the diffuse loss of cellularity of the spiral ligament and an accumulation of an extracellular deposit in the spiral ligament, osseous spiral lamina and the limbus and the subepithelial mesenchymal tissue of the vestibular neuroepithelium.…”