Journal article
Carboxypeptidase D deficiency causes hearing loss amenable to treatment
The Journal of clinical investigation, Vol.135(23), e192090
12/01/2025
DOI: 10.1172/JCI192090
PMCID: PMC12646673
PMID: 41026541
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.
Details
- Title: Subtitle
- Carboxypeptidase D deficiency causes hearing loss amenable to treatment
- Creators
- Memoona Ramzan - Dr. John T. Macdonald FoundationNatalie Ortiz-Vega - University of MiamiMohammad Faraz Zafeer - Dr. John T. Macdonald FoundationAmanda G Lobato - University of MiamiTahir Atik - Ege UniversityClemer Abad - Dr. John T. Macdonald FoundationNirmal Vadgama - Stanford UniversityDuygu Duman - Ankara UniversityNazım Bozan - Van Yüzüncü Yıl ÜniversitesiEnise Avcı Durmuşalioǧlu - Ege UniversitySunny Greene - University of MiamiShengru Guo - Dr. John T. Macdonald FoundationSuna Tokgöz-Yılmaz - Ankara UniversityMerve Koç Yekedüz - Ankara UniversityFatma Tuba Eminoğlu - Ankara UniversityMehmet Aydın - Van Yüzüncü Yıl ÜniversitesiSerhat Seyhan - Memorial Sisli HospitalIoannis Karakikes - Stanford UniversityVladimir Camarena - Dr. John T. Macdonald FoundationMaria Camila Robayo - Dr. John T. Macdonald FoundationTijana Canic - University of ChicagoGüney Bademci - Dr. John T. Macdonald FoundationGaofeng Wang - Dr. John T. Macdonald FoundationAmjad Farooq - University of MiamiMei-Ling Joiner - University of IowaKatherina Walz - Dr. John T. Macdonald FoundationDaniel F Eberl - University of IowaJamal Nasir - University of NorthamptonR Grace Zhai - University of MiamiMustafa Tekin - University of Miami
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.135(23), e192090
- DOI
- 10.1172/JCI192090
- PMID
- 41026541
- PMCID
- PMC12646673
- NLM abbreviation
- J Clin Invest
- ISSN
- 1558-8238
- eISSN
- 1558-8238
- Publisher
- American Society for Clinical Investigation; ANN ARBOR
- Grant note
- NIH: R01DC009645, R01DC012836, R33AT010408 ANPCyT Argentina: PICT-2021 GRF-TI-00422 American Heart Association postdoctoral fellowship: 23POSTCHF1031213
This work is the result of NIH funding, in whole or in part, and is subject to the NIH Public Access Policy. Through acceptance of this federal funding, the NIH has been given a right to make the work publicly available in PubMed Central. center dot NIH R01DC009645 and R01DC012836 (to MT) and R33AT010408 (to RGZ) . center dot ANPCyT Argentina PICT-2021 GRF-TI-00422 (to KW) . center dot American Heart Association postdoctoral fellowship (23POSTCHF1031213 to NV) .
- Language
- English
- Electronic publication date
- 09/30/2025
- Date published
- 12/01/2025
- Academic Unit
- Iowa Neuroscience Institute; Biology
- Record Identifier
- 9984968941902771
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