Phenotypic differences in the inner ears of CBA/CaJ and C57BL/6J mice carrying missense and single base pair deletion mutations in the Cdh23 gene

Different mutations in the cadherin 23 (CDH23) gene in different genetic backgrounds have been linked to either syndromic or nonsyndromic forms of deafness in humans. We previously reported a progressive hearing loss (HL) mouse model, the Cdh23(erl/erl) mouse, which carries a 208T > C mutation causing an amino acid substitution at S70P in C57BL/6J mice. To investigate the differences in Cdh23 mutation-related HL in different genetic backgrounds, we used the CRISPR/Cas9 system to generate homozygous mice in the CBA/CaJ background that have the same base pair missense mutation (208T > C) (Cdh23(erl2/erl2)) as Cdh23(erl/erl) mice in the C57BL/6J background or a single base pair deletion (235G) (Cdh23(V2J2/V2J2)) in the Cdh23 gene at exon 5. The two mutant mice exhibit hearing impairment across a broad range of frequencies. The progression of HL in Cdh23(erl2/erl2) mice is slower than that in Cdh23(erl/erl) mice. We also found structural abnormalities in the stereocilia of cochlear hair cells in Cdh23(erl2/erl2) and Cdh23(V2J2/V2J2) mice. Cdh23(V2J2/V2J2) mice show signs of vestibular dysfunction in open field behavior and swimming tests. In addition, we observed hair bundle defects in vestibular hair cells in Cdh23(V2J2/V2J2) mice. Our results suggest an interaction between the erl locus and the C57BL/6J background that exacerbates HL in Cdh23(erl/erl) mice. Moreover, our study confirms that the Cdh23 gene is essential for normal hearing and balance. These two novel mutant mouse strains provide excellent models for studying CDH23 mutation-related deafness in humans.