Hereditary sensorineural hearing loss in Chinese Rongchang pigs result from promoter mutations in MITF
(Background)Genesis of novel gene regulatorymodules is largely responsible formorphological and functional evolution.New active cis-regulatory elements(CREs)can arise from transposition,promoter switching,co-option or de novo generation.Obviously,the last model,de novo genesis of CREs could be a rare event in genome evolution,due to the odds of creating totally novel CREs aremuch lower than that of altering existing CREs.It is only reported by a sole case in fishes.However,genetic variation drives either new genesis of CREs or phenotypic alteration has not been reported.Results: Here,we took advantage of a spontaneous hearing loss model found in pigs,and studied the mutation in a non-regulatory region of the melanocyte-specific promoter of microphthalmia-associated transcription factor(MITF)gene.The mutation generated a novel silencer and eliminated expression of MITF-M.This consequently caused the early degeneration of intermediate cells of the cochlear stria vascularis and profound hearing loss,similar to the typical phenotype of Waardenburgsyndrome in humans.We found that the mutation exclusively affected MITF-M,not other isoforms.The essential function of Mitf-m in hearing development was further validated using a knock-out mouse mode.l Conclusions:These results demonstrated that dysfunction in the MITF-M isoform alone was sufficient to cause deafness and depigmentation.To our knowledge,this study provides the first evidence of a systemic functional de novo CRE in mammals.
de novo silencer MITF-M hearing loss Waardenburg syndrome cisregulatory element pig
Chen lei Guo weiwei Zhang tinghuan Zhu dan Jing lan Chen siqing Bai xiaoqing Zhang fengming Wang tao Ge liangpeng Liu zuohua Yang shiming Li ning Wang jingyong
Key Laboratory of Pig Industry Sciences(Ministry of Agriculture),Chongqing Academy of Animal Science Department of Otolaryngology,Head & Neck Surgery,Institute of Otolaryngology,Chinese PLA General Hos State Key Laboratory for Agrobiotechnology,College of Biological Sciences,National Engineering Labor
国内会议
重庆
英文
80-93
2016-05-25（万方平台首次上网日期，不代表论文的发表时间）