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<p>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 <i>KLHDC7B</i>, a gene of unknown function not previously linked to hearing. We demonstrate <i>Klhdc7b</i> is expressed exclusively in sensory hair cells in mouse cochlea. Utilizing two independent mouse knockout models (<i>Klhdc7b</i><sup><i>IMPC-/-</i></sup> and <i>Klhdc7b</i><sup><i>Regn</i>Δ/Δ</sup>) we find that absence of <i>Klhdc7b</i> 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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月17日

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  • Alexandra M. Kaufman,
  • Benjamin Silver,
  • Roberto A. Donnianni,
  • Carlos Aguilar,
  • Lingzi Niu,
  • Daniel Johnson,
  • Anwen Bullen,
  • Alma Corona,
  • Benjamin J. van Soldt,
  • Nilay Vora,
  • Gervasio Batista,
  • Luz Cortes-Burgos,
  • Jacqueline Copeland,
  • Elika Fallah,
  • Norman Zhang,
  • Marina Lehmkuhl,
  • Sarah Cancelarich,
  • Kara Campos,
  • Daniela Di Battista Miani,
  • Jaylen Mumphrey,
  • Susan D. Croll,
  • Johnathon R. Walls,
  • Mary Germino,
  • Michael R. Bowl,
  • Meghan C. Drummond,
  • Sally J. Dawson

摘要

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.