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Long-range cis-regulatory elements controlling GDF6 expression are essential for ear development

2020; American Society for Clinical Investigation; Linguagem: Inglês

10.1172/jci136951

1558-8238

Güney Bademci, Clemer Abad, Filiz Başak Cengiz, Serhat Seyhan, Armağan İncesulu, Shengru Guo, Suat Fítöz, Emine İkbal Atlı, Nicholas C. Gosstola, Selma Demır, Brett M. Colbert, Gozde Cosar Seyhan, Claire J. Sineni, Duygu Duman, Hakan Gürkan, Cynthia C. Morton, Derek M. Dykxhoorn, Katherina Walz, Mustafa Tekin,

Animal Vocal Communication and Behavior

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.