Toward the Pathogenicity of the SLC26A4 p.C565Y Variant Using a Genetically Driven Mouse Model
2021
Chin-Ju Hu | Ying-Chang Lu | Ting-Hua Yang | Yen-Hui Chan | Cheng-Yu Tsai | I-Shing Yu | Shu-Wha Lin | Tien-Chen Liu | Yen-Fu Cheng | Chen-Chi Wu | Chuan-Jen Hsu
Recessive variants of the <em>SLC26A4</em> 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 <em>SLC26A4</em> variants. However, discrepancies in pathogenicity between humans and cell lines or transgenic mice were documented for some <em>SLC26A4</em> 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 (<em>Slc26a4<sup>+/C565Y</sup></em>), homozygous (<em>Slc26a4<sup>C565Y/C565Y</sup></em>), and compound heterozygous (<em>Slc26a4<sup>919-2A>G/C565Y</sup></em>) 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 <em>SLC26A4</em> variants between transgenic mice and humans, which should be considered when interpreting the results of animal studies for <em>SLC26A4</em>-related deafness.
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