PKHD1L1 is required for stereocilia bundle maintenance, durable hearing function and resilience to noise exposure.

Polycystic Kidney and Hepatic Disease 1-Like 1 (PKHD1L1) is a human deafness gene, responsible for autosomal recessive deafness-124 (DFNB124). Sensory hair cells of the cochlea are essential for hearing, relying on the mechanosensitive stereocilia bundle at their apical pole for their function. PKHD1L1 is a stereocilia protein required for the formation of the developmentally transient stereocilia surface coat. In this study, we carry out an in depth characterization of PKHD1L1 expression in mice during development and adulthood, analyze hair-cell bundle morphology and hearing function in aging PKHD1L1-deficient mouse lines, and assess their susceptibility to noise damage. Our findings reveal that PKHD1L1-deficient mice display no disruption to bundle cohesion or tectorial membrane attachment-crown formation during development. However, starting from 6 weeks of age, PKHD1L1-deficient mice display missing stereocilia and disruptions to bundle coherence. Both conditional and constitutive PKHD1L1 knockout mice develop high-frequency hearing loss progressing to lower frequencies with age. Furthermore, PKHD1L1-deficient mice are susceptible to permanent hearing loss following moderate acoustic overexposure, which induces only temporary hearing threshold shifts in wild-type mice. These results suggest a role for PKHD1L1 in establishing robust sensory hair bundles during development, necessary for maintaining bundle cohesion and function in response to acoustic trauma and aging.