Hereditary hearing loss is one of the most common birth defects, yet the majority of genes required for audition is thought to remain unidentified. Ethylnitrosourea (ENU)–mutagenesis has been a valuable approach for generating new animal models of deafness and discovering previously unrecognized gene functions. Here we report on the characterization of a new ENU–induced mouse mutant (nmf329) that exhibits recessively inherited deafness. We found a widespread loss of sensory hair cells in the hearing organs of nmf329 mice after the second week of life. Positional cloning revealed that the nmf329 strain carries a missense mutation in the claudin-9 gene, which encodes a tight junction protein with unknown biological function. In an epithelial cell line, heterologous expression of wild-type claudin-9 reduced the paracellular permeability to Na⁺ and K⁺, and the nmf329 mutation eliminated this ion barrier function without affecting the plasma membrane localization of claudin-9. In the nmf329 mouse line, the perilymphatic K⁺ concentration was found to be elevated, suggesting that the cochlear tight junctions were dysfunctional. Furthermore, the hair-cell loss in the claudin-9–defective cochlea was rescued in vitro when the explanted hearing organs were cultured in a low-K⁺ milieu and in vivo when the endocochlear K⁺-driving force was diminished by deletion of the pou3f4 gene. Overall, our data indicate that claudin-9 is required for the preservation of sensory cells in the hearing organ because claudin-9–defective tight junctions fail to shield the basolateral side of hair cells from the K⁺-rich endolymph. In the tight-junction complexes of hair cells, claudin-9 is localized specifically to a subdomain that is underneath more apical tight-junction strands formed by other claudins. Thus, the analysis of claudin-9 mutant mice suggests that even the deeper (subapical) tight-junction strands have biologically important ion barrier function. Hereditary deafness is a common birth defect in the human population, yet the majority of genes required for audition is thought to be unidentified. Genetic approaches in the mouse have greatly contributed to our understanding of the molecular mechanisms that underlie hearing. Random mutagenesis of mice, identification of deaf mutants, and subsequent analysis of the deafness-causing gene defects has led to the discovery of several previously unrecognized gene functions. Here, we report on the characterization of a new mutant mouse line (nmf329) that exhibits profound hearing loss and loss of sensory cells in the auditory organ. Genetic analysis reveals that these animals carry a mutation in the claudin-9 gene, which encodes a protein with hitherto unknown biological function. We have found that normal claudin-9—but not a mutant form—inhibits the paracellular movement of certain ions. The lack of the claudin-9 ion barrier in the inner ear leads to changes in ionic conditions that can account for the loss of sensory cells in the mutant mice. Within the cell–cell junctions, the claudin-9 layer is located basal to those of other claudins. Thus, our analysis of claudin-9–deficient animals suggests that even the deeper layers of claudins have important ion barrier function.

A cochlear implant (CI) can be an effective means of rehabilitation for patients with severe to profound sensorineural hearing loss. The number of CI recipients now exceeds 300 000 worldwide and is rapidly increasing.¹ However, undergoing magnetic resonance imaging (MRI), which is used during the evaluation of a variety of conditions, can pose significant concerns for CI recipients. Developments in MRI technologies have enabled the generation of high-resolution images, which generally require the use of instruments with 1.5-T to 3.0-T field strengths. In the past, CIs were thought to be incompatible with MRI because the internal magnet located within the CI receiver can generate significant torque when placed in a strong electromagnetic field, which can dislodge the implant.² Additionally, these internal magnets can induce artifacts in MRI scans, which is also true for the receiver coil and electrode, albeit to a lesser extent. Therefore, the primary issue for patients with CIs who undergo MRI is exposure of the internal magnet to a strong electromagnetic field, which can induce significant magnetic forces and cause serious problems.

Meniere's disease is an inner ear disorder that can manifest as fluctuating vertigo, sensorineural hearing loss, tinnitus, and aural fullness. However, the pathologic mechanism of Meniere's disease is still unclear. In this study, we evaluated autoimmunity as a potential cause of Meniere's disease. In addition we tried to find useful biomarker candidates for diagnosis. We investigated the protein composition of human inner ear fluid using liquid column mass spectrometry, the autoimmune reaction between circulating autoantibodies in patient serum and multiple antigens using the Protoarray system, the immune reaction between patient serum and mouse inner ear tissues using western blot analysis. Nine proteins, including immunoglobulin and its variants and interferon regulatory factor 7, were found only in the inner ear fluid of patients with Meniere's disease. Enhanced immune reactions with 18 candidate antigens were detected in patients with Meniere's disease in Protoarray analysis; levels of 8 of these antigens were more than 10-fold higher in patients than in controls. Antigen-antibody reactions between mouse inner ear proteins with molecular weights of 23–48 kDa and 63–75 kDa and patient sera were detected in 8 patients. These findings suggest that autoimmunity could be one of the pathologic mechanisms behind Meniere's disease. Multiple autoantibodies and antigens may be involved in the autoimmune reaction. Specific antigens that caused immune reactions with patient's serum in Protoarray analysis can be candidates for the diagnostic biomarkers of Meniere's disease.