https://scholars.lib.ntu.edu.tw/handle/123456789/586655
標題: | Insights into phenotypic differences between humans and mice with p.T721M and other C-terminal variants of the SLC26A4 gene | 作者: | Hu, Chin-Ju Lu, Ying-Chang Tsai, Cheng-Yu Chan, Yen-Hui PEI-HSUAN LIN Lee, Yi-Shan Yu, I-Shing SHU-WHA LIN TIEN-CHEN LIU Hsu, Chuan-Jen TING-HUA YANG Cheng, Yen-Fu Chen-Chi Wu |
公開日期: | 25-十月-2021 | 卷: | 11 | 期: | 1 | 來源出版物: | Scientific reports | 摘要: | Recessive variants of the SLC26A4 gene are an important cause of hereditary hearing impairment. Several transgenic mice with different Slc26a4 variants have been generated. However, none have recapitulated the auditory phenotypes in humans. Of the SLC26A4 variants identified thus far, the p.T721M variant is of interest, as it appears to confer a more severe pathogenicity than most of the other missense variants, but milder pathogenicity than non-sense and frameshift variants. Using a genotype-driven approach, we established a knock-in mouse model homozygous for p.T721M. To verify the pathogenicity of p.T721M, we generated mice with compound heterozygous variants by intercrossing Slc26a4+/T721M mice with Slc26a4919-2A>G/919-2A>G mice, which segregated the c.919-2A > G variant with abolished Slc26a4 function. We then performed serial audiological assessments, vestibular evaluations, and inner ear morphological studies. Surprisingly, both Slc26a4T721M/T721M and Slc26a4919-2A>G/T721M showed normal audiovestibular functions and inner ear morphology, indicating that p.T721M is non-pathogenic in mice and a single p.T721M allele is sufficient to maintain normal inner ear physiology. The evidence together with previous reports on mouse models with Slc26a4 p.C565Y and p.H723R variants, support our speculation that the absence of audiovestibular phenotypes in these mouse models could be attributed to different protein structures at the C-terminus of human and mouse pendrin. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/586655 | ISSN: | 2045-2322 | DOI: | 10.1038/s41598-021-00448-7 | SDG/關鍵字: | SLC26A4 protein, human; Slc26a4 protein, mouse; animal; chemistry; disease model; gene knock-in; genetics; hearing impairment; homozygote; human; male; metabolism; missense mutation; mouse; pathology; phenotype; protein domain; species difference; Animals; Disease Models, Animal; Gene Knock-In Techniques; Hearing Loss; Homozygote; Humans; Male; Mice; Mutation, Missense; Phenotype; Protein Domains; Species Specificity; Sulfate Transporters |
顯示於: | 醫學檢驗暨生物技術學系 |
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