Takahashi, S.; Zhou, Y.; Cheatham, M. A.; Homma, K.

Prestin,s voltage-driven motor activity confers sound-elicited somatic electromotility in auditory outer hair cells (OHCs) and is essential for the exquisite sensitivity and frequency selectivity of mammalian hearing. Lack of prestin results in hearing threshold shifts across frequency, supporting the causal association of variants in the prestin-coding gene, SLC26A5, with human hearing loss, DFNB61. However, cochlear function can tolerate reductions in prestin-mediated OHC electromotility. We found that two deafness-associated prestin variants, p.A100T and p.P119S, do not deprive prestin of its fast motor function but significantly reduce membrane expression, leading to large reductions in OHC electromotility that were only ~30% of wildtype (WT). Mice harboring these missense variants suffered congenital hearing loss that was worse at high frequencies; however, they retained WT-like auditory brainstem response thresholds at 8 kHz, which is processed at the apex of the mouse cochlea. This observation suggests the increasing importance of prestin-driven cochlear amplification at higher frequencies relevant to mammalian hearing. The observation also suggests the promising clinical possibility that small enhancements of OHC electromotility could significantly ameliorate DFNB61 hearing loss in human patients.