The mouse Cdh23ahl allele drives early cochlear dysfunction and phenotypic heterogeneity before progressive hearing loss

The Cdh23ahl allele, present in various inbred mouse strains, is known to cause progressive hearing loss. However, recent studies suggest it may also influence the severity and expression of other genetic traits, affecting more than just the cochlea. Researchers compared C57BL/6N mice with this allele to an identical strain with the allele corrected through genome editing to understand its full impact.

The findings indicate that the auditory effects of Cdh23ahl are not only earlier and more variable than previously thought, but also affect a broader range of cochlear functions. By the age of one month, there are already significant threshold elevations at higher frequencies, while lower frequencies experience progressive involvement.

Before these changes, inner hair cells at just 14 days postnatal show tonotopically distinct alterations in mechanoelectrical transduction, with reduced maximal transduction currents at the apex and increased currents at the base, while resting open probability and adaptation kinetics remain unchanged. Additionally, cochlear transcription is altered shortly after the onset of hearing.

By 16 days postnatal, Cdh23ahl and repaired cochleae occupy distinct transcriptional states, with these differences expanding significantly by 30 days. At this point, Cdh23ahl cochleae display increased inter-individual transcriptomic dispersion, coinciding with the emergence of variable high-frequency auditory dysfunction. These results suggest that Cdh23ahl is not physiologically benign in young mice but instead represents an altered cochlear state that precedes hearing loss.

The study's findings provide a potential framework for understanding the allele's effects on phenotype expressivity and have important implications for the design and interpretation of studies involving mouse strains carrying Cdh23ahl.