KLHDC7B, a novel gene associated with age-related hearing loss in humans, is required for the maintenance of hearing in mice.

BackgroundAge-related hearing loss (ARHL) is the most common sensory loss in older adults, but the underlying pathological mechanisms remain unclear. Recent genome wide association studies (GWAS) have linked variation in a large number of genes with increased risk of ARHL for the first time. Amongst the strongest of these associations is variation in KLHDC7B, a gene of unknown function and one not previously linked to hearing. MethodsTo confirm whether KLHDC7B plays a role in hearing we investigated auditory function in two independent knockout mutant mouse models of Klhdc7b: Klhdc7bIMPC-/-and Klhdc7bRegn{Delta}/{Delta} on the C57BL/6N background and the B6.CAST-Cdh23753A>G background respectively. The B6.CAST-Cdh23753A>G background was backcrossed to correct a known age-related hearing loss (ahl) mutation in cadherin 23 present in both the C57BL/6N and C57BL/6J strains. ResultsWe showed that Klhdc7b is expressed exclusively in inner and outer sensory hair cells within the cochlea of mice at the RNA and protein level. Homozygous mutants for both knockout mouse models display a similar early-onset, progressive and severe hearing loss. Histological characterization of the two mouse models suggests that hair cells develop normally and are present in neonates. However, after the onset of hearing there is a progressive loss of outer hair cells in a gradient from base to apex of the cochlea consistent with the hearing deficit in the mice and the pattern of hearing loss in ARHL. Inner hair cells remain intact up to the latest age examined (~8 weeks). ConclusionsOur data suggests KLHDC7B is required for maintenance of auditory function rather than in its development, supporting the novel association with ARHL in humans detected in recent GWAS. To our knowledge, this is the first validation in mouse of an ARHL association in humans detected in a GWAS. Our work also provides two distinct mouse models to further investigate the role of KLHDC7B in auditory function and for use in the development of therapeutic tools to prevent or treat ARHL.