Mutations in human SLC26A4 are a common cause of hearing loss associated with enlarged vestibular aqueducts (EVA). SLC26A4 encodes pendrin, an anion-base exchanger expressed in inner ear epithelial cells that secretes HCO 3 -into endolymph. Studies of Slc26a4-null mice indicate that pendrin is essential for inner ear development, but have not revealed whether pendrin is specifically necessary for homeostasis. Slc26a4-null mice are profoundly deaf, with severe inner ear malformations and degenerative changes that do not model the less severe human phenotype. Here, we describe studies in which we generated a binary transgenic mouse line in which Slc26a4 expression could be induced with doxycycline. The transgenes were crossed onto the Slc26a4-null background so that all functional pendrin was derived from the transgenes. Varying the temporal expression of Slc26a4 revealed that E16.5 to P2 was the critical interval in which pendrin was required for acquisition of normal hearing. Lack of pendrin during this period led to endolymphatic acidification, loss of the endocochlear potential, and failure to acquire normal hearing. Doxycycline initiation at E18.5 or discontinuation at E17.5 resulted in partial hearing loss approximating the human EVA auditory phenotype. These data collectively provide mechanistic insight into hearing loss caused by SLC26A4 mutations and establish a model for further studies of EVA-associated hearing loss.

BackgroundTinnitus is a common condition and frequently can be annoying to affected individuals. We investigated the prevalence and associated factors for tinnitus in South Korea using the data from the Korea National Health and Nutrition Examination Surveys (KNHANES) during 2009–2011.MethodsKNHANES is a cross-sectional survey of the civilian, non-institutionalized population of South Korea (n = 21 893). A field survey team that included an otolaryngologist moved with a mobile examination unit and performed interviews and physical examinations.ResultsAmong the population over 12 years of age, the prevalence of any tinnitus was 19.7% (95% CI 18.8%–20.6%). Tinnitus was more prevalent in women, and the prevalence rate increased with age (P < 0.001). Among those with any tinnitus, 29.3% (95% CI 27.3%–31.3%) experienced annoying tinnitus that affected daily life. Annoying tinnitus also increased with age (P < 0.001), but no sex difference was demonstrated (P = 0.25). In participants aged 40 years or older, age, quality of life, depressive mood, hearing loss, feeling of dizziness, and rhinitis were associated with any tinnitus (P < 0.05). Age, hearing loss, history of cardiovascular disease, and stress were associated with annoying tinnitus (P < 0.05).ConclusionsTinnitus is a common condition, and a large population suffers from annoying tinnitus in South Korea. Public understanding of associated factors might contribute to better management of tinnitus.

Genes that are primarily expressed in cochlear glia-like supporting cells (GLSs) have not been clearly associated with progressive deafness. Herein, we present a deafness locus mapped to chromosome 3p25.1 and an auditory neuropathy spectrum disorder (ANSD) gene, TMEM43, mainly expressed in GLSs. We identify p.(Arg372Ter) of TMEM43 by linkage analysis and exome sequencing in two large Asian families segregating ANSD, which is characterized by inability to discriminate speech despite preserved sensitivity to sound. The knock-in mouse with the p.(Arg372Ter) variant recapitulates a progressive hearing loss with histological abnormalities in GLSs. Mechanistically, TMEM43 interacts with the Connexin26 and Connexin30 gap junction channels, disrupting the passive conductance current in GLSs in a dominant-negative fashion when the p.(Arg372Ter) variant is introduced. Based on these mechanistic insights, cochlear implant was performed on three subjects, and speech discrimination was successfully restored. Our study highlights a pathological role of cochlear GLSs by identifying a deafness gene and its causal relationship with ANSD.