Effects of Cdh23 single nucleotide substitutions on age-related hearing loss in C57BL/6 and 129S1/Sv mice and comparisons with congenic strains

A single nucleotide variant (SNV) of the cadherin 23 gene (Cdh23(c.753A)), common to many inbred mouse strains, accelerates age-related hearing loss (AHL) and can worsen auditory phenotypes of other mutations. We used homologous recombination in C57BL/6 NJ (B6N) and 129S1/SvImJ (129S1) embryonic stem cells to engineer mouse strains with reciprocal single base pair substitutions (B6-Cdh23(c.753A>G) and 129S1-Cdh23(c.753G>A)). We compared ABR thresholds and cochlear pathologies of these SNV mice with those of congenic (B6.129S1-Cdh23(Ahl+) and 129S1.B6-Cdh23(ahl)) and parental (B6N and 129S1) strain mice. Results verified the protective effect of the Cdh23(c.753G) allele, which prevented high frequency hearing loss in B6 mice to at least 18 months of age, and the AHL-inducing effect of the Cdh23(c.753A) allele, which worsened hearing loss in 129S1 mice. ABR thresholds differed between 129S-Cdh23(c.753A) SNV and 129S1.B6-Cdh23(ahl) congenic mice, and a linkage backcross involving these strains localized a Chr 10 QTL contributing to the difference. These results illustrate the large effects that strain background and congenic regions have on the hearing loss associated with Cdh23(c.753)alleles. Importantly, the B6-Cdh23(c.753G)strain can be used to eliminate the confounding influence of the Cdh23(c.753A)variant in hearing studies of B6 mice and mutant mice on the B6 background.