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Mutations in the  SLC26A4  gene are a common cause of human hereditary hearing impairment worldwide. Previous studies have demonstrated that different  SLC26A4  mutations have different pathogenetic mechanisms. By using a genotype-driven approach, we established a knock-in mouse model (i.e.,  Slc26a4 tm2Dontuh/tm2Dontuh   mice) homozygous for the common p.H723R mutation in the East Asian population. To verify the pathogenicity of the p.H723R allele in mice, we further generated mice with compound heterozygous mutations (i.e.,  Slc26a4 tm1Dontuh/tm2Dontuh  ) by intercrossing  Slc26a4 +/tm2Dontuh   mice with  Slc26a4 tm1Dontuh/tm1Dontuh   mice, which segregated the c.919-2A>G mutation with an abolished  Slc26a4  function. Mice were then subjected to audiologic assessments, a battery of vestibular evaluations, inner ear morphological studies, and noise exposure experiments. The results were unexpected; both  Slc26a4 tm2Dontuh/tm2Dontuh   and  Slc26a4 tm1Dontuh/tm2Dontuh   mice showed normal audiovestibular phenotypes and inner ear morphology, and they did not show significantly higher shifts in hearing thresholds after noise exposure than the wild-type mice. The results indicated not only the p.H723R allele was non-pathogenic in mice, but also a single p.H723R allele was sufficient to maintain normal inner ear physiology in heterozygous compound mice. There might be discrepancies in the pathogenicity of specific  SLC26A4  mutations in humans and mice; therefore, precautions should be taken when extrapolating the results of animal studies to humans.

Differences in the Pathogenicity of the p.H723R Mutation of the Common Deafness-Associated SLC26A4 Gene in Humans and Mice