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

Abstract

A single nucleotide variant (SNV) of the cadherin 23 gene (Cdh23c.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-Cdh23c.753A>G and 129S1-Cdh23c.753G>A). We compared ABR thresholds and cochlear pathologies of these SNV mice with those of congenic (B6.129S1-Cdh23Ahl+ and 129S1.B6-Cdh23ahl) and parental (B6N and 129S1) strain mice. Results verified the protective effect of the Cdh23c.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 Cdh23c.753A allele, which worsened hearing loss in 129S1 mice. ABR thresholds differed between 129S-Cdh23c.753A SNV and 129S1.B6-Cdh23ahl 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 Cdh23c.753alleles. Importantly, the B6-Cdh23c.753Gstrain can be used to eliminate the confounding influence of the Cdh23c.753Avariant in hearing studies of B6 mice and mutant mice on the B6 background.

Induced Short-Term Hearing Loss due to Stimulation of Age-Related Factors by Intermittent Hypoxia, High-Fat Diet, and Galactose Injection

“…By determining the expression of Ucp2 under all environmental stimuli, it was confirmed that mitochondrial dysfunction was caused by oxidative stress [ 12 , 14 ]. Mitochondrial dysfunction has been observed to induce apoptosis in many studies [ 9 , 19 ], and we obtained similar results through histological analysis in this study. Thus, we discussed that the reduction of frequencies was influenced when the blood vessels were damaged, and substance exchange in the bloodstream was poor because of the hypoxic condition and HFD.…”

“…As for Sod1 , it has been reported that as the amount of oxidative stress in the cells of the auditory organ increases, the amount of Sod1 also increases [ 7 , 8 ]. In addition, numerous reports have suggested that in these models, abnormal potassium channels resulting from mass transfer errors cause cell death [ 9 , 10 ]. However, these animal models have certain limitations since they do not reflect the lifestyle of the animals [ 4 , 11 ].…”

“…Mitochondrial damage has been considered responsible for the death of auditory hair cells due to aging [ 6 , 17 ]. Therefore, based on relevant factors identified in the literature, we designed an aging animal model resulting from the exposure to a combination of three different lifestyles [ 9 , 18 ]. It has been reported that mitochondrial dysfunction can be induced by diet modification [ 19 ].…”

VISTA expression by microglia decreases during inflammation and is differentially regulated in CNS diseases

“…These results are in line with our previous observations of decreased VISTA expression in microglia during EAE and in Ercc1 Δ/− mice. VISTA is located within an intronic region of CDH23 , a gene associated with auditory function (Johnson et al, ). Cdh23 was not altered in response to LPS, demonstrating that changes in VISTA expression were independent of the Cdh23 gene (Supporting Information, Figure S3a).…”

Cre-dependent optogenetic transgenic mice without early age-related hearing loss

“…Alternatively, mice created by gene editing technology can be an option. In B6-Cdh23 c.753G mice, for example, the point mutation of cdh23 has been corrected (Johnson et al, 2017).…”