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ResearchIn-Press PreviewGeneticsOtology Open Access | 10.1172/JCI192090

Carboxypeptidase D deficiency causes hearing loss amenable to treatment

Memoona Ramzan,1 Natalie Ortiz-Vega,2 Mohammad Faraz Zafeer,1 Amanda G. Lobato,2 Tahir Atik,3 Clemer Abad,1 Nirmal Vadgama,4 Duygu Duman,5 Nazım Bozan,6 Enise Avcı Durmuşalioǧlu,3 Sunny Greene,2 Shengru Guo,1 Suna Tokgöz-Yılmaz,5 Merve Koç Yekedüz,7 Fatma Tuba Eminoğlu,8 Mehmet Aydın,6 Serhat Seyhan,9 Ioannis Karakikes,4 Vladimir Camarena,1 Maria Camila Robayo,1 Tijana Canic,10 Güney Bademci,11 Gaofeng Wang,1 Amjad Farooq,12 Mei-ling Joiner,13 Katherina Walz,1 Daniel F. Eberl,13 Jamal Nasir,14 R. Grace Zhai,2 and Mustafa Tekin1

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

Find articles by Ortiz-Vega, N. in: PubMed | Google Scholar

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

Find articles by Atik, T. in: PubMed | Google Scholar

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

Find articles by Vadgama, N. in: PubMed | Google Scholar |

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

Find articles by Bozan, N. in: PubMed | Google Scholar

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

Find articles by Avcı Durmuşalioǧlu, E. in: PubMed | Google Scholar

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

Find articles by Tokgöz-Yılmaz, S. in: PubMed | Google Scholar

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

Find articles by Eminoğlu, F. in: PubMed | Google Scholar

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

Find articles by Karakikes, I. in: PubMed | Google Scholar |

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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

2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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2Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States of America

3Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey

4Department of Cardiothoracic Surgery, Stanford University, Stanford, United States of America

5Department of Audiology, Ankara University Faculty of Health Sciences, Ankara, Turkey

6Department of Otolaryngology, Faculty of Medicine, Yüzüncü Yıl University, Van, Turkey

7Division of Pediatric Metabolic Diseases, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey

8Ankara University Rare Diseases Application and Research Center, Ankara, Turkey

9Laboratory of Genetics, Memorial Şişli Hospital, Istanbul, Turkey

10Department of Neurology, University of Chicago, Chicago, United States of America

11Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, United States of America

12Department of Biochemistry, University of Miami Miller School of Medicine, Miami, United States of America

13University of Iowa, Iowa City, United States of America

14Division of Life Sciences, University of Northampton, Northampton, United Kingdom

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Published September 30, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI192090.
Copyright © 2025, Ramzan 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 September 30, 2025 - Version history
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Abstract

Genetic factors contributing to hearing loss (HL) are heterogeneous, and effective medical treatments remain limited. We identified three distinct missense variants in CPD, encoding carboxypeptidase D, in five individuals with congenital deafness from three unrelated families, affecting the catalytically active CP-domain2 of this protein. Subsequent analysis of a larger cohort from the 100,000 Genomes Project (100KGP), revealed an enrichment of rare protein-altering CPD variants in individuals with HL. We show that CPD localizes to sensory epithelium and nerve cells in the mouse cochlea, and the enzymatic activity of CPD, crucial for nitric oxide (NO) production through arginine processing, is impaired in affected individuals. The levels of arginine, NO, and cyclic guanosine monophosphate (cGMP) in patient-derived fibroblasts are also decreased, leading to increased oxidative stress and cell death via endoplasmic reticulum stress-mediated mechanisms. Silencing of Cpd in organotypic mouse cochlea cultures leads to increased apoptosis. Finally, Drosophila models of CPD deficiency display defective Johnston’s organ, impaired auditory transduction, and sensory and movement abnormalities. Notably, these phenotypes are partially rescued by the supplementation with arginine or sildenafil, a cGMP enhancer. Our findings establish CPD mutations as a cause of congenital HL, highlighting that the NO signaling pathway offers a promising therapeutic avenue.

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