Cross-species validation of a human age-related hearing loss candidate KLHDC7B as essential for mammalian hearing
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 (Klhdc7b<sup>IMPC-/-</sup> and Klhdc7b<sup>RegnΔ/Δ</sup>) 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.
Authors
- Michael R. Bowl (ORCID: https://orcid.org/0000-0001-7971-445X)
- Mary Germino (ORCID: https://orcid.org/0000-0001-7523-3798)
- Alexandra M. Kaufman
- Benjamin Silver (ORCID: https://orcid.org/0000-0002-4763-3281)
- Daniel Johnson (ORCID: https://orcid.org/0000-0003-1088-3460)
- Jacqueline Copeland
- Sally J. Dawson (ORCID: https://orcid.org/0000-0002-4421-2043)
- Elika Fallah
- Carlos Aguilar (ORCID: https://orcid.org/0000-0002-4655-1778)
- Lingzi Niu (ORCID: https://orcid.org/0009-0005-7451-1625)
- Gervasio Batista (ORCID: https://orcid.org/0000-0003-0885-1224)
- Ana Paula Corona (ORCID: https://orcid.org/0000-0002-0032-7906)
- Meghan C. Drummond
- Nilay Vora (ORCID: https://orcid.org/0000-0002-2265-5580)
- Daniela Di Battista Miani
- Roberto A. Donnianni
- Sarah Cancelarich
- Benjamin J. van Soldt (ORCID: https://orcid.org/0000-0002-1670-6193)
- Luz Cortes-Burgos
- Anwen Bullen (ORCID: https://orcid.org/0000-0002-6705-5263)
- Susan D. Croll (ORCID: https://orcid.org/0000-0002-3949-1877)
- Norman Zhang (ORCID: https://orcid.org/0009-0003-0216-2329)
- Keila Campos
- Johnathon R. Walls
- Marina Lehmkuhl
- Jaylen Mumphrey
Institutions
- Regeneron (United States) (US)
- Mary Lyon Centre at MRC Harwell (GB)
- The London College (GB)
- University College London (GB)
Publication Details
- Journal
- Communications Biology
- Published
- 2025-12-17
- DOI
- https://doi.org/10.1038/s42003-025-09349-1
- Primary Topic
- Hearing, Cochlea, Tinnitus, Genetics
- Type
- article
- Field-Weighted Citation Impact
- 0.00