Hearing loss and audiogenic seizures induced by hypofunctional prestin variants.

Abstract

Prestin's voltage-driven motor activity confers sound-elicited somatic electromotility on auditory outer hair cells (OHCs) and is essential for the exquisite sensitivity and frequency selectivity of mammalian hearing. Lack of prestin results in ∼50 dB hearing threshold shifts across frequency, supporting the causal association of the prestin-coding gene, SLC26A5, with hereditary hearing loss, DFNB61. However, ∼50% reduction in prestin-mediated OHC electromotility barely affects cochlear function, and it is currently unknown how much electromotility is minimally required to support normal hearing. We generated mouse models harboring two deafness-associated prestin variants, p.A100T and p.P119S, and found that these missense variants do not deprive prestin of its fast motor function but significantly reduce membrane expression, leading to 70-80% reductions in OHC electromotility. Homozygous and compound heterozygous mice of either sex for these missense variants suffered congenital hearing loss; however, they still retained relatively low hearing thresholds at lower frequencies, pointing to the clinical possibility that a small augmentation of OHC electromotility could benefit those with DFNB61 hearing loss. These mice were also found to be prone to audiogenic seizures. This study thus provides insights into the minimum OHC electromotility required for normal cochlear operation and reveals the unappreciated importance of prestin for central gain control.Significance statement Prestin is abundantly expressed in the auditory outer hair cells and is essential for normal cochlear operation. Hence, reduction of prestin expression is often taken as indicative of reduced cochlear function in diseased or aged ears. However, this assumption overlooks the fact that cochlear function can tolerate surprisingly large reductions in prestin motor activity. DFNB61 mouse models generated and characterized in this study provide an opportunity to gauge the amount of prestin motor activity needed to sustain normal hearing sensitivity. This knowledge is crucial not only for understanding the pathogenic roles of deafness-associated variants that impair OHC electromotility but also for unraveling how prestin contributes to cochlear amplification.