| Literature DB >> 32369452 |
Guney Bademci1, Clemer Abad1, Filiz B Cengiz1, Serhat Seyhan1, Armagan Incesulu2, Shengru Guo1, Suat Fitoz3, Emine Ikbal Atli4, Nicholas C Gosstola1, Selma Demir4, Brett M Colbert1,5, Gozde Cosar Seyhan6, Claire J Sineni1, Duygu Duman7, Hakan Gurkan4, Cynthia C Morton8,9,10,11,12, Derek M Dykxhoorn1,13, Katherina Walz1,13, Mustafa Tekin1,13,14.
Abstract
Molecular mechanisms governing the development of the mammalian cochlea, the hearing organ, remain largely unknown. Through genome sequencing in 3 subjects from 2 families with nonsyndromic cochlear aplasia, we identified homozygous 221-kb and 338-kb deletions in a noncoding region on chromosome 8 with an approximately 200-kb overlapping section. Genomic location of the overlapping deleted region started from approximately 350 kb downstream of GDF6, which codes for growth and differentiation factor 6. Otic lineage cells differentiated from induced pluripotent stem cells derived from an affected individual showed reduced expression of GDF6 compared with control cells. Knockout of Gdf6 in a mouse model resulted in cochlear aplasia, closely resembling the human phenotype. We conclude that GDF6 plays a necessary role in early cochlear development controlled by cis-regulatory elements located within an approximately 500-kb region of the genome in humans and that its disruption leads to deafness due to cochlear aplasia.Entities:
Keywords: Genetic diseases; Genetics; Organogenesis; Otology
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Year: 2020 PMID： 32369452 PMCID： PMC7410044 DOI： 10.1172/JCI136951
Source DB: PubMed Journal: J Clin Invest ISSN： 0021-9738 Impact factor: 14.808