LAUSR

Significance Auditory neuropathy spectrum disorder (ANSD) is a confounding auditory disease in which the subjects respond to sound but have difficulties in speech discrimination. Herein, we examined two Asian families with hereditary late-age–onset ANSD. By linkage analysis and exome sequencing, we identified the TMEM43-p.(Arg372Ter) variant as the etiology of the disease. To examine the mechanism of TMEM43 on ANSD, we generated a knock-in mouse with the p.(Arg372Ter) variant that recapitulated the progressive hearing loss phenotype of the two families. We discovered that variation in TMEM43 impairs the connexin-linked function of mediating passive conductance current in cochlear glial cells. Based on the pathology involving cochlear glial cells, we performed cochlear implant on the human patients, and their speech discrimination ability was restored. 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.