Year: 2025
Type: article
Abstract: Genetic factors contributing to hearing loss (HL) are heterogeneous, and effective medical treatments remain limited. We identified 3 distinct missense variants in CPD, encoding carboxypeptidase D, in 5 individuals with congenital deafness from 3 unrelated families, affecting the catalytically active CP domain 2 of this protein. Subsequent analysis of a larger cohort from the 100,000 Genomes Project 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 cGMP in patient-derived fibroblasts are also decreased, leading to endoplasmic reticulum stress-mediated responses being triggered in the cells. 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 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.
DOI: 10.1172/jci192090
Authors: Memoona Ramzan, Natalie Ortiz-Vega, Mohammad Faraz Zafeer, Amanda G. Lobato, Tahir Atik, Clemer Abad, Nirmal Vadgama, Duygu Duman, Nazım Bozan, Enise Avcı Durmuşalioǧlu, Sunny Greene, Shengru Guo, Suna Tokgöz-Yılmaz, Merve Koç Yekedüz, Fatma Tuba Eminoğlu, Mehmet Aydın, Serhat Seyhan, Ioannis Karakikes, Vladimir Camarena, Maria Camila Robayo, Tijana Canic, Güney Bademci, Gaofeng Wang, Amjad Farooq, Mei-ling Joiner, Katherina Walz, Daniel F. Eberl, Jamal Nasir, R. Grace Zhai, Mustafa Tekin
Institutions: University of Miami, University of Chicago, Ege University, Stanford Medicine, Stanford University, Ankara University, Van Yüzüncü Yıl Üniversitesi, Boston Children's Hospital, Harvard University, Memorial Sisli Hospital, Dr. John T. Macdonald Foundation, University of Iowa, Consejo Nacional de Investigaciones Científicas y Técnicas, University of Northampton
Language: English
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: American Heart Association, Wellcome Trust, Cancer Research UK, National Institute for Health and Care Research, National Institutes of Health, Medical Research Council, Agencia Nacional de Promoción Científica y Tecnológica, National Institute on Deafness and Other Communication Disorders, National Institute of General Medical Sciences, National Center for Complementary and Integrative Health
Awards: G3918619244, Defining the neural crest's role in CHD and associated comorbidities using single-cell epigenomics and deep learning, microRNA regulation of NMNAT-mediated Neuroprotection against Peripheral Neuropathy and Chronic Pain, G8599100277, G9000117381, G9000175241, IRACDA at the University of Chicago
OpenAlex ID: W4414681466