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

摘要

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.753alleles. Importantly, the B6-Cdh23^c.753Gstrain can be used to eliminate the confounding influence of the Cdh23^c.753Avariant in hearing studies of B6 mice and mutant mice on the B6 background.