title: Differences in the pathogenicity of the p.H723R mutation of the common deafness-associated SLC26A4 gene in humans and mice.
abstract: 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.
authors.affiliation: Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan.
authors.forename: Ying-Chang
authors.initials: YC
authors.lastname: Lu
authors.forename: Chen-Chi
authors.initials: CC
authors.lastname: Wu
authors.forename: Ting-Hua
authors.initials: TH
authors.lastname: Yang
authors.forename: Yin-Hung
authors.initials: YH
authors.lastname: Lin
authors.forename: I-Shing
authors.initials: IS
authors.lastname: Yu
authors.forename: Shu-Wha
authors.initials: SW
authors.lastname: Lin
authors.forename: Qing
authors.initials: Q
authors.lastname: Chang
authors.forename: Xi
authors.initials: X
authors.lastname: Lin
authors.forename: Jau-Min
authors.initials: JM
authors.lastname: Wong
authors.forename: Chuan-Jen
authors.initials: CJ
authors.lastname: Hsu
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics* / Q000378:metabolism; D001309:Auditory Threshold; D001483:Base Sequence; D003051:Cochlea / Q000473:pathology; D003638:Deafness / Q000235:genetics* / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007668:Kidney / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics*; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009622:Noise; D010641:Phenotype; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D000076988:Sulfate Transporters; D013961:Thyroid Gland / Q000378:metabolism; D014723:Vestibular Aqueduct / Q000378:metabolism / Q000473:pathology; D000098854:Kcnj10 Channel
chemical_list: D027321:Anion Transport Proteins; D000098854:Kcnj10 Channel; D026901:Membrane Transport Proteins; D024661:Potassium Channels, Inwardly Rectifying; C085609:SLC26A4 protein, human; C494849:Slc26a4 protein, mouse; D000076988:Sulfate Transporters