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

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

Division of Psychology Communication and Human Neuroscience (L5)

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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.

Original language	English
Journal	Journal of Clinical Investigation
Early online date	29 Jun 2020
DOIs	https://doi.org/10.1172/JCI136951
Publication status	Published - 2020

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https://www.jci.org/articles/view/136951

Manchester Centre for Audiology and Deafness (ManCAD)
Munro, K. (PI), Millman, R. (PI), Lamb, W. (Support team), Dawes, P. (PI), Plack, C. (PI), Stone, M. (PI), Kluk-De Kort, K. (PI), Moore, D. (PI), Morton, C. (PI), Prendergast, G. (PI), Couth, S. (PI), Schlittenlacher, J. (PI), Chilton, H. (PI), Visram, A. (Researcher), Dillon, H. (PI), Guest, H. (Researcher), Heinrich, A. (PI), Jackson, I. (Researcher), Littlejohn, J. (Researcher), Jones, L. (PI), Lough, M. (Researcher), Morgan, R. (Researcher), Perugia, E. (Researcher), Roughley, A. (Researcher), Whiston, H. (Researcher), Wright, C. (Support team), Saunders, G. (PI), Kelly, C. (PI), Cross, H. (Researcher), Loughran, M. (Researcher), Hoseinabadi, R. (PI) & Vercammen, C. (PI)
Project: Research

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Bademci, G., Abad, C., Cengiz, F. B., Seyhan, S., Incesulu, A., Guo, S., Fitoz, S., Atli, E. I., Gosstola, N. C., Demir, S., Colbert, B. M., Seyhan, G. C., Sineni, C. J., Duman, D., Gurkan, H., Morton, C. C., Dykxhoorn, D. M., Walz, K., & Tekin, M. (2020). Long-range cis-regulatory elements controlling GDF6 expression are essential for ear development. Journal of Clinical Investigation. https://doi.org/10.1172/JCI136951

@article{c9979c2ab5314b74a5594ec40ecc092f,

title = "Long-range cis-regulatory elements controlling GDF6 expression are essential for ear development",

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.",

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

year = "2020",

doi = "10.1172/JCI136951",

language = "English",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

}

Bademci, G, Abad, C, Cengiz, FB, Seyhan, S, Incesulu, A, Guo, S, Fitoz, S, Atli, EI, Gosstola, NC, Demir, S, Colbert, BM, Seyhan, GC, Sineni, CJ, Duman, D, Gurkan, H, Morton, CC, Dykxhoorn, DM, Walz, K & Tekin, M 2020, 'Long-range cis-regulatory elements controlling GDF6 expression are essential for ear development', Journal of Clinical Investigation. https://doi.org/10.1172/JCI136951

TY - JOUR

T1 - Long-range cis-regulatory elements controlling GDF6 expression are essential for ear development

AU - Bademci, Guney

AU - Abad, Clemer

AU - Cengiz, Filiz B.

AU - Seyhan, Serhat

AU - Incesulu, Armagan

AU - Guo, Shengru

AU - Fitoz, Suat

AU - Atli, Emine Ikbal

AU - Gosstola, Nicholas C.

AU - Demir, Selma

AU - Colbert, Brett M.

AU - Seyhan, Gozde Cosar

AU - Sineni, Claire J.

AU - Duman, Duygu

AU - Gurkan, Hakan

AU - Morton, Cynthia C.

AU - Dykxhoorn, Derek M.

AU - Walz, Katherina

AU - Tekin, Mustafa

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

U2 - 10.1172/JCI136951

DO - 10.1172/JCI136951

M3 - Article

SN - 0021-9738

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

ER -

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

Abstract

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Manchester Centre for Audiology and Deafness (ManCAD)

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