Dataset Information

A de novo silencer causes elimination of MITF-M expression and profound hearing loss in pigs.

ABSTRACT: Genesis of novel gene regulatory modules is largely responsible for morphological and functional evolution. De novo generation of novel cis-regulatory elements (CREs) is much rarer than genomic events that alter existing CREs such as transposition, promoter switching or co-option. Only one case of de novo generation has been reported to date, in fish and without involvement of phenotype alteration. Yet, this event likely occurs in other animals and helps drive genetic/phenotypic variation.Using a porcine model of spontaneous hearing loss not previously characterized we performed gene mapping and mutation screening to determine the genetic foundation of the phenotype. We identified a mutation in the non-regulatory region of the melanocyte-specific promoter of microphthalmia-associated transcription factor (MITF) gene that generated a novel silencer. The consequent elimination of expression of the MITF-M isoform led to early degeneration of the intermediate cells of the cochlear stria vascularis and profound hearing loss, as well as depigmentation, all of which resemble the typical phenotype of Waardenburg syndrome in humans. The mutation exclusively affected MITF-M and no other isoforms. The essential function of Mitf-m in hearing development was further validated using a knock-out mouse model.Elimination of the MITF-M isoform alone is sufficient to cause deafness and depigmentation. To our knowledge, this study provides the first evidence of a de novo CRE in mammals that produces a systemic functional effect.

SUBMITTER: Chen L

PROVIDER: S-EPMC4922063 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A de novo silencer causes elimination of MITF-M expression and profound hearing loss in pigs.

Chen Lei L Guo Weiwei W Ren Lili L Yang Mingyao M Zhao Yaofeng Y Guo Zongyi Z Yi Haijin H Li Mingzhou M Hu Yiqing Y Long Xi X Sun Boyuan B Li Jinxiu J Zhai Suoqiang S Zhang Tinghuan T Tian Shilin S Meng Qingyong Q Yu Ning N Zhu Dan D Tang Guoqing G Tang Qianzi Q Ren Liming L Liu Ke K Zhang Shihua S Che Tiandong T Yu Zhengquan Z Wu Nan N Jing Lan L Zhang Ran R Cong Tao T Chen Siqing S Zhao Yiqiang Y Zhang Yue Y Bai Xiaoqing X Guo Ying Y Zhao Lidong L Zhang Fengming F Zhao Hui H Zhang Liang L Hou Zhaohui Z Zhao Jiugang J Li Jianan J Zhang Lijuan L Sun Wei W Zou Xiangang X Wang Tao T Ge Liangpeng L Liu Zuohua Z Hu Xiaoxiang X Wang Jingyong J Yang Shiming S Li Ning N

BMC biology 20160627

<h4>Background</h4>Genesis of novel gene regulatory modules is largely responsible for morphological and functional evolution. De novo generation of novel cis-regulatory elements (CREs) is much rarer than genomic events that alter existing CREs such as transposition, promoter switching or co-option. Only one case of de novo generation has been reported to date, in fish and without involvement of phenotype alteration. Yet, this event likely occurs in other animals and helps drive genetic/phenotyp ...[more]

PMID: 27349893

Similar Datasets

Project description:BackgroundHereditary hearing loss (HL) is heterogeneous in terms of their phenotypic features, modes of inheritance, and causative gene mutations. The contribution of genetic variants to sporadic HL remains largely expanding. Either recessive or de novo dominant variants could result in an apparently sporadic occurrence of HL. In an attempt to find such variants we recruited 128 Chinese patients with sporadic nonsyndromic sensorineural HL (NSHL) and performed targeted deafness multigene sequencing in these unrelated trios-families to elucidate the molecular basis.MethodsWe analyzed a total of 384 available members (probands and their two parents) from 128 unrelated Chinese families presenting with bilateral sensorineural HL, in which previous screening had found no mutations with the GJB2, SLC26A4, and MT-RNR1 genes. We used a targeted genomic enrichment platform to simultaneously capture exons, splicing sites, and immediate flanking intron sequences of 127 known deafness genes. Sanger sequencing was used to identify probands and their two parents segregating causative variants in the candidate gene.ResultsWe observed that two heterozygous de novo WFS1 mutations in exon 8: c.2051C>T (p.A684V) and c.2590G>A (p.E864K) in five families. The two de novo WFS1 mutations were found in 3.9% (5/128) of sporadic HL patients. We found that four of the five patients had the same de novo p.A684V mutation, and their audiograms showed symmetrical bilateral and profound sensorineural hearing impairments at all frequencies, but only the proband with de novo p.E864K mutation demonstrated significantly bilateral moderate low-mid frequency sensorineural HL. Our data suggest that this WFS1 p.A684V is likely to be a de novo mutational hot spot.ConclusionsWe found 3.9% (5/128) of sporadic NSHL is caused by de novo WFS1 mutations. Our data provide that the de novo p.E864K mutation is first identified and de novo p.A684V mutation is likely to be a mutational hot spot in WFS1. It is the first study to highlight that WFS1 gene with the two de novo mutations has been indicated to classify the distinct hearing impairment phenotypes. Furthermore, de novo p.A684V serves as a WFS1 mutational hot spot that was found in the Chinese population with sporadic childhood NSHL, and our study also provides pointers toward the necessity for sequencing of asymptomatic parents of a sporadic case with an apparent dominant pathogenic variant.

Dataset Information

A de novo silencer causes elimination of MITF-M expression and profound hearing loss in pigs.

Publications

A de novo silencer causes elimination of MITF-M expression and profound hearing loss in pigs.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets