# Cross-species validation of a human age-related hearing loss candidate KLHDC7B as essential for mammalian hearing

## TL;DR

This study shows that a gene linked to age-related hearing loss in humans is essential for maintaining hearing in mice.

## Contribution

The study validates a human ARHL GWAS candidate gene in mice and provides new models for studying hearing loss.

## Key findings

- Klhdc7b is expressed exclusively in sensory hair cells in the mouse cochlea.
- Loss of Klhdc7b causes severe, progressive hearing loss in mice, mimicking age-related hearing loss.
- Klhdc7b is important for maintaining auditory function, not for initial development.

## Abstract

Although age-related hearing loss (ARHL) is the most common sensory loss in older adults, underlying mechanisms remain unclear. Recent genome-wide association studies (GWAS) linked variation in several genes with ARHL risk, including KLHDC7B, a gene of unknown function not previously linked to hearing. We demonstrate Klhdc7b is expressed exclusively in sensory hair cells in mouse cochlea. Utilizing two independent mouse knockout models (Klhdc7bIMPC-/- and Klhdc7bRegnΔ/Δ) we find that absence of Klhdc7b leads to severe early-onset, progressive hearing loss. Hair cells appear to develop normally, but outer hair cells are progressively lost from base-to-apex of the cochlea, a common pathology in ARHL. These results suggest KLHDC7B is required for maintenance rather than development, of auditory function. The validation in mouse of a human ARHL GWAS association suggests other novel candidates should be investigated. Our work provides two mouse models to study KLHDC7B function, and for development of therapeutic tools for ARHL.

Using two independent knockout mouse models, the authors show that loss of Klhdc7b, a candidate for susceptibility to age-related hearing loss in humans, results in an early and progressive hearing loss, confirming Klhdc7b’s role in the maintenance of hearing.