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

Guney Bademci; Clemer Abad; Filiz B Cengiz; Serhat Seyhan; Armagan Incesulu; Shengru Guo; Suat Fitoz; Emine Ikbal Atli; Nicholas C Gosstola; Selma Demir; Brett M Colbert; Gozde Cosar Seyhan; Claire J Sineni; Duygu Duman; Hakan Gurkan; Cynthia C Morton; Derek M Dykxhoorn; Katherina Walz; Mustafa Tekin

doi:10.1172/JCI136951

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

Journal article

Peer reviewed

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

Guney Bademci, Clemer Abad, Filiz B Cengiz, Serhat Seyhan, Armagan Incesulu, Shengru Guo, Suat Fitoz, Emine Ikbal Atli, Nicholas C Gosstola, Selma Demir, …

The Journal of clinical investigation, Vol.130(8), pp.4213-4217

2020-08-03

DOI: https://doi.org/10.1172/JCI136951

PMID: 32369452

Abstract

Genetics

Otology

Concise Communication

Genetic diseases

Organogenesis

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.150 Hearing Loss; 1.150.421 Cochlea
Web Of Science research areas: Medicine, Research & Experimental
ESI research areas: Clinical Medicine

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Title: Long-range cis-regulatory elements controlling GDF6 expression are essential for ear development
Creators: Guney Bademci - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA
Clemer Abad - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA
Filiz B Cengiz - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA
Serhat Seyhan - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA
Armagan Incesulu - Department of Otolaryngology, Eskisehir Osmangazi University School of Medicine, Eskisehir, Turkey
Shengru Guo - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA
Suat Fitoz - Department of Diagnostic Radiology, Ankara University School of Medicine, Ankara, Turkey
Emine Ikbal Atli - Department of Medical Genetics, Faculty of Medicine, Trakya University, Edirne, Turkey
Nicholas C Gosstola - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA
Selma Demir - Department of Medical Genetics, Faculty of Medicine, Trakya University, Edirne, Turkey
Brett M Colbert - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA
Gozde Cosar Seyhan - Department of Dermatology, Bakirkoy Sadi Konuk Training and Research Hospital, Istanbul, Turkey
Claire J Sineni - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA
Duygu Duman - Department of Audiology, Ankara University School of Medicine, Ankara, Turkey
Hakan Gurkan - Department of Medical Genetics, Faculty of Medicine, Trakya University, Edirne, Turkey
Cynthia C Morton - Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
Derek M Dykxhoorn - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA
Katherina Walz - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA
Mustafa Tekin - John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA
Publication Details: The Journal of clinical investigation, Vol.130(8), pp.4213-4217
Publisher: American Society for Clinical Investigation
Grant note: R01DC009645 / National Institutes of Health R01DC015052 / National Institutes of Health R01DC012836 / National Institutes of Health
Academic Unit: Miller School of Medicine; John P. Hussman Institute for Human Genomics; UMMG Dept of Human Genetics - Clinical and Translational Genetics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 32369452
Record Identifier: 991031576015302976