Journal
HUMAN GENETICS
Volume 136, Issue 11-12, Pages 1463-1475Publisher
SPRINGER
DOI: 10.1007/s00439-017-1851-2
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Funding
- National Natural Science Foundation of China [1671274, 31601008, 31402045]
- Strategic Priority Research Program of CAS [XDA08000000, XDA01030400]
- National Transgenic Project of China [2016ZX08009003-006, 2014ZX0801007B]
- National Basic Research Program of China [2011CBA01005, 2011CB944100, 2011BAI15B02, 2012BAI39B04, 2012CB967900]
- National High Technology Research and Development Program of China [2012AA020602]
- National Institutes of Health [DC006908]
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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 MITFL247S/L247S) and CRISPR/Cas9-mediated MITF biallelic 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.
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