Distal enhancer-insulator module of <i>GDF6</i> is essential for cochlear formation

Mohammad Faraz Zafeer; Clemer Abad; Havva Ortabozkoyun; Memoona Ramzan; Guney Bademci; Maria C. Robayo; Duygu Duman; Rolen M. Quadros; Shengru Guo; Juan I. Young; Anthony J. Griswold; Channabasavaiah B. Gurumurthy; Derek M. Dykxhoorn; Katherina Walz; Mustafa Tekin

doi:10.1172/jci.insight.195462

¹John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, United States of America

²Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

³Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

⁴Mouse Genome Engineering Core Facility, University of Nebraska Medical Center, Omaha, United States of America

⁵John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Maimi, United States of America

Find articles by Zafeer, M. in: PubMed | Google Scholar

¹John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, United States of America

²Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

³Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

⁴Mouse Genome Engineering Core Facility, University of Nebraska Medical Center, Omaha, United States of America

⁵John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Maimi, United States of America

Find articles by Abad, C. in: PubMed | Google Scholar

¹John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, United States of America

²Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

³Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

⁴Mouse Genome Engineering Core Facility, University of Nebraska Medical Center, Omaha, United States of America

⁵John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Maimi, United States of America

Find articles by Ortabozkoyun, H. in: PubMed | Google Scholar

¹John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, United States of America

²Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

³Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

⁴Mouse Genome Engineering Core Facility, University of Nebraska Medical Center, Omaha, United States of America

⁵John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Maimi, United States of America

Find articles by Ramzan, M. in: PubMed | Google Scholar

¹John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, United States of America

²Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

³Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

⁴Mouse Genome Engineering Core Facility, University of Nebraska Medical Center, Omaha, United States of America

⁵John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Maimi, United States of America

Find articles by Bademci, G. in: PubMed | Google Scholar

¹John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, United States of America

²Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

³Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

⁴Mouse Genome Engineering Core Facility, University of Nebraska Medical Center, Omaha, United States of America

⁵John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Maimi, United States of America

Find articles by Robayo, M. in: PubMed | Google Scholar

¹John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, United States of America

²Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

³Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

⁴Mouse Genome Engineering Core Facility, University of Nebraska Medical Center, Omaha, United States of America

⁵John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Maimi, United States of America

Find articles by Duman, D. in: PubMed | Google Scholar |

¹John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, United States of America

²Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

³Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

⁴Mouse Genome Engineering Core Facility, University of Nebraska Medical Center, Omaha, United States of America

⁵John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Maimi, United States of America

Find articles by Quadros, R. in: PubMed | Google Scholar

¹John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, United States of America

²Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

³Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

⁴Mouse Genome Engineering Core Facility, University of Nebraska Medical Center, Omaha, United States of America

⁵John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Maimi, United States of America

Find articles by Guo, S. in: PubMed | Google Scholar |

¹John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, United States of America

²Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

³Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

⁴Mouse Genome Engineering Core Facility, University of Nebraska Medical Center, Omaha, United States of America

⁵John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Maimi, United States of America

Find articles by Young, J. in: PubMed | Google Scholar

¹John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, United States of America

²Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

³Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

⁴Mouse Genome Engineering Core Facility, University of Nebraska Medical Center, Omaha, United States of America

⁵John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Maimi, United States of America

Find articles by Griswold, A. in: PubMed | Google Scholar

¹John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, United States of America

²Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

³Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

⁴Mouse Genome Engineering Core Facility, University of Nebraska Medical Center, Omaha, United States of America

⁵John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Maimi, United States of America

Find articles by Gurumurthy, C. in: PubMed | Google Scholar

¹John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, United States of America

²Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

³Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

⁴Mouse Genome Engineering Core Facility, University of Nebraska Medical Center, Omaha, United States of America

⁵John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Maimi, United States of America

Find articles by Dykxhoorn, D. in: PubMed | Google Scholar

¹John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, United States of America

²Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

³Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

⁴Mouse Genome Engineering Core Facility, University of Nebraska Medical Center, Omaha, United States of America

⁵John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Maimi, United States of America

Find articles by Walz, K. in: PubMed | Google Scholar

¹John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, United States of America

²Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

³Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

⁴Mouse Genome Engineering Core Facility, University of Nebraska Medical Center, Omaha, United States of America

⁵John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Maimi, United States of America

Find articles by Tekin, M. in: PubMed | Google Scholar |

JCI Insight. https://doi.org/10.1172/jci.insight.195462.
Copyright © 2026, Zafeer et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published June 18, 2026 - Version history

Several genes guide inner ear development, and mutations in these genes can cause malformations that result in congenital hearing loss. However, the contribution of noncoding regulatory elements remains largely unclear. This study investigates the function of distal enhancer elements in the transcriptional regulation of GDF6, a gene implicated in cochlear development. Using mouse models with targeted deletions, human inner ear organoids, and CRISPR interference (CRISPRi), we identified a downstream regulatory interval harboring a developmental enhancer required to maintain GDF6 expression during otic epithelial maturation and cochlear morphogenesis. Deletion of this regulatory region or targeting of CRISPRi-based repressors to these regions resulted in decreased GDF6 expression, failure of otic-epithelium development, and prevention of hair cell-like differentiation, reflecting cochlear aplasia observed in patients with corresponding genomic deletions. These findings highlight the contribution of long-range regulatory elements to auditory development and illustrate how their disruption contributes to human deafness.

Version 1 (June 18, 2026): In-Press Preview

Distal enhancer-insulator module of GDF6 is essential for cochlear formation

Mohammad Faraz Zafeer,¹ Clemer Abad,¹ Havva Ortabozkoyun,² Memoona Ramzan,¹ Guney Bademci,² Maria C. Robayo,¹ Duygu Duman,³ Rolen M. Quadros,⁴ Shengru Guo,¹ Juan I. Young,¹ Anthony J. Griswold,¹ Channabasavaiah B. Gurumurthy,⁴ Derek M. Dykxhoorn,¹ Katherina Walz,¹ and Mustafa Tekin¹

Article tools

Metrics

Go to

Distal enhancer-insulator module of GDF6 is essential for cochlear formation

Mohammad Faraz Zafeer,1 Clemer Abad,1 Havva Ortabozkoyun,2 Memoona Ramzan,1 Guney Bademci,2 Maria C. Robayo,1 Duygu Duman,3 Rolen M. Quadros,4 Shengru Guo,1 Juan I. Young,1 Anthony J. Griswold,1 Channabasavaiah B. Gurumurthy,4 Derek M. Dykxhoorn,1 Katherina Walz,1 and Mustafa Tekin1

Article tools

Metrics

Go to

Sign up for email alerts