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

• Type of Material: Article
• Authors: Ying-Chang Lu, National Taiwan University; Chen-Chi Wu, National Taiwan University; Ting-Hua Yang, National Taiwan University; Yin-Hung Lin, National Taiwan University; I-Shing Yu, National Taiwan University; Xi Lin, Emory University; Qing Chang, Emory University; Jua-Min Wong, National Taiwan University; Chuan-Jen Hsu, National Taiwan University
• Language: English
• Date: 2013-06-03
• Publisher: Public Library Science
• Publication Version: Final Published Version
• Copyright Statement: © 2013 Lu et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0064906
• Title of Journal or Parent Work: PLoS ONE
• Volume: 8
• Issue: 6
• Start Page: e64906
• End Page: e64906
• Grant/Funding Information: This study was supported by research grants from the National Health Research Institute (NHRI-EX101-10147PI), National Science Council of the Executive Yuan of the Republic of China (NSC-99-2314-B-002-056-MY3), and National Taiwan University Hospital (NTUH-100-001597).
• Keywords: Syndrome mouse model; Science & Technology - Other Topics; Enlarged vestibular aqueduct; Science & Technology; Cells; PDS Gene; Multidisciplinary Sciences; KCNJ10 Protein Expression; Genotype-phenotype correlation; Inner-ear; Pendred-syndrome gene; Unique spectrum; Nonsyndromic healing
• Research Categories: Health Sciences, Pathology; Biology, Genetics; Engineering, Biomedical

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., Slc26a4tm2Dontuh/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., Slc26a4tm1Dontuh/tm2Dontuh) by intercrossing Slc26a4+/tm2Dontuh mice with Slc26a4tm1Dontuh/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 Slc26a4tm2Dontuh/tm2Dontuh and Slc26a4tm1Dontuh/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.