TY - JOUR
T1 - Cross-species validation of a human age-related hearing loss candidate KLHDC7B as essential for mammalian hearing
AU - Kaufman, Alexandra M.
AU - Silver, Benjamin
AU - Donnianni, Roberto A.
AU - Aguilar, Carlos
AU - Niu, Lingzi
AU - Johnson, Daniel
AU - Bullen, Anwen
AU - Corona, Alma
AU - van Soldt, Benjamin J.
AU - Vora, Nilay
AU - Batista, Gervasio
AU - Cortes-Burgos, Luz
AU - Copeland, Jacqueline
AU - Fallah, Elika
AU - Zhang, Norman
AU - Lehmkuhl, Marina
AU - Cancelarich, Sarah
AU - Campos, Kara
AU - Di Battista Miani, Daniela
AU - Mumphrey, Jaylen
AU - Croll, Susan D.
AU - Walls, Johnathon R.
AU - Germino, Mary
AU - Bowl, Michael R.
AU - Drummond, Meghan C.
AU - Dawson, Sally J.
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12/17
Y1 - 2025/12/17
N2 - 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. (Figure presented.)
AB - 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. (Figure presented.)
UR - https://www.scopus.com/pages/publications/105028106224
U2 - 10.1038/s42003-025-09349-1
DO - 10.1038/s42003-025-09349-1
M3 - Article
C2 - 41407909
AN - SCOPUS:105028106224
SN - 2399-3642
VL - 9
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 84
ER -