| Literature DB >> 29094203 |
Tang Hai1,2, Weiwei Guo3, Jing Yao1,2, Chunwei Cao1,2, Ailing Luo1,2, Meng Qi1,2, Xianlong Wang1,2, Xiao Wang1,2, Jiaojiao Huang1,2, Ying Zhang1,2, Hongyong Zhang1,2, Dayu Wang1,2, Haitao Shang4,2, Qianlong Hong1,2, Rui Zhang1,2, Qitao Jia1,2, Qiantao Zheng1,2, Guosong Qin1,2, Yongshun Li1,2, Tao Zhang1,2, Weiwu Jin1,2, Zheng-Yi Chen5, Hongmei Wang1,2,6, Qi Zhou1,2,6, Anming Meng7,2, Hong Wei8,9, Shiming Yang10, Jianguo Zhao11,12,13.
Abstract
Human Waardenburg syndrome 2A (WS2A) is a dominant hearing loss (HL) syndrome caused by mutations in the microphthalmia-associated transcription factor (MITF) gene. In mouse models with MITF mutations, WS2A is transmitted in a recessive pattern, which limits the study of hearing loss (HL) pathology. In the current study, we performed ENU (ethylnitrosourea) mutagenesis that resulted in substituting a conserved lysine with a serine (p. L247S) in the DNA-binding domain of the MITF gene to generate a novel miniature pig model of WS2A. The heterozygous mutant pig (MITF +/L247S) exhibits a dominant form of profound HL and hypopigmentation in skin, hair, and iris, accompanied by degeneration of stria vascularis (SV), fused hair cells, and the absence of endocochlear potential, which indicate the pathology of human WS2A. Besides hypopigmentation and bilateral HL, the homozygous mutant pig (MITF L247S/L247S) and CRISPR/Cas9-mediated MITF bi-allelic knockout pigs both exhibited anophthalmia. Three WS2 patients carrying MITF mutations adjacent to the corresponding region were also identified. The pig models resemble the clinical symptom and molecular pathology of human WS2A patients perfectly, which will provide new clues for better understanding the etiology and development of novel treatment strategies for human HL.Entities:
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Year: 2017 PMID： 29094203 DOI： 10.1007/s00439-017-1851-2
Source DB: PubMed Journal: Hum Genet ISSN： 0340-6717 Impact factor: 4.132