Toward the Pathogenicity of the p.C565Y Variant Using a Genetically Driven Mouse Model.

Recessive variants of the gene are globally a common cause of hearing impairment. In the past, cell lines and transgenic mice were widely used to investigate the pathogenicity associated with variants. However, discrepancies in pathogenicity between humans and cell lines or transgenic mice were documented for some variants. For instance, the p.C565Y variant, which was reported to be pathogenic in humans, did not exhibit functional pathogenic consequences in cell lines. To address the pathogenicity of p.C565Y, we used a genotype-based approach in which we generated knock-in mice that were heterozygous (), homozygous (), and compound heterozygous () for this variant. Subsequent phenotypic characterization revealed that mice with these genotypes demonstrated normal auditory and vestibular functions, and normal inner-ear morphology and pendrin expression. These findings indicate that the p.C565Y variant is nonpathogenic for mice, and that a single p.C565Y allele is sufficient to maintain normal inner-ear physiology in mice. Our results highlight the differences in pathogenicity associated with certain variants between transgenic mice and humans, which should be considered when interpreting the results of animal studies for -related deafness.