An international team reports that rare mutations in CPD (carboxypeptidase D) cause a congenital, sensorineural form of hearing loss by disrupting arginine–nitric oxide signaling in inner‑ear hair cells. In models, arginine supplementation or sildenafil partially reversed disease‑related defects, highlighting a pathway for future therapies.
An international collaboration led by researchers at the University of Miami, with contributors from the University of Chicago and several institutions in Türkiye, has identified mutations in the CPD gene as a cause of congenital sensorineural hearing loss. The peer‑reviewed study, published September 30, 2025, in the Journal of Clinical Investigation, describes three distinct CPD missense variants found in five individuals from three unrelated families and reports an enrichment of rare, protein‑altering CPD variants among people with hearing loss in the 100,000 Genomes Project.
CPD encodes carboxypeptidase D, a peptidase that influences intracellular arginine availability and nitric oxide (NO)–cGMP signaling. In patient‑derived fibroblasts, the authors observed reduced levels of arginine, NO, and cGMP, along with signs of oxidative and endoplasmic‑reticulum stress. In mouse cochlear tissue, silencing Cpd increased apoptosis, supporting the vulnerability of sensory hair cells when this pathway is impaired.
Using Drosophila models, the team showed that CPD deficiency disrupts Johnston’s organ and auditory transduction and causes broader sensory and movement abnormalities. Notably, two interventions—oral arginine supplementation and sildenafil, a cGMP‑pathway enhancer marketed as Viagra—partially rescued disease phenotypes in flies. These findings point to pharmacological strategies worth testing in additional preclinical studies.
R. Grace Zhai, PhD—an author of the study who is now at the University of Chicago and, at the time of the research, affiliated with the University of Miami—said in a University of Chicago news release: “It turns out that CPD maintains the level of arginine in the hair cells to allow a quick signaling cascade by generating nitric oxide… And that’s why, although it’s expressed ubiquitously in other cells throughout the nervous system, these hair cells in particular are more sensitive or vulnerable to the loss of CPD.”
While there is no approved medical repair for congenital sensorineural hearing loss—standard care relies on hearing aids or cochlear implants—the authors say their data nominate the NO–cGMP pathway as a potential therapeutic target. The team plans to probe nitric oxide signaling further and to assess how common CPD variants are in larger populations. In the University of Chicago release, Zhai also noted that single CPD variants could contribute to age‑related hearing loss, a possibility the researchers intend to explore.
Collaborating institutions included Ege University, Ankara University, Yüzüncü Yıl University, Memorial Şişli Hospital, the University of Iowa, and the University of Northampton.
