New Discoveries Connect CPD Mutations to Congenital Deafness
A multinational team of scientists has identified a gene mutation in CPD that plays a crucial role in a rare form of congenital hearing loss. The collaborative study, conducted by researchers from the University of Chicago, the University of Miami, and several Turkish institutions, was published in the Journal of Clinical Investigation. The work illuminates how CPD, traditionally known for its role in protein editing, also influences the inner ear, and points toward promising treatment strategies.
Lead author Rong Grace Zhai, PhD, Jack Miller Professor for the Study of Neurological Diseases of Neurology at UChicago, emphasized the significance: “This study is exciting because we found a new gene mutation that’s linked to deafness, and more importantly we have a therapeutic target that can actually mitigate this condition.” While the study centers on a rare mutation combination in CPD, she suggested the findings could have broader implications for age-related hearing loss if single CPD variants contribute to vulnerability in the ear.
How CPD Mutation Affects Hearing
The team began by examining a distinctive trio of CPD mutations in three unrelated Turkish families with sensorineural hearing loss (SNHL), a congenital and hereditary form of deafness diagnosed in early childhood. SNHL can cause permanent hearing impairment, and while devices such as hearing aids and cochlear implants can assist, there is currently no medical cure for the underlying condition.
Mining a genetic database, researchers observed that other individuals with CPD mutations also exhibited signs of early-onset hearing loss, suggesting a broader link between CPD function and auditory health.
The Molecular Mechanism: Arginine and Nitric Oxide
To understand how CPD mutations translate to hearing loss, the researchers turned to mouse models. CPD encodes an enzyme responsible for producing the amino acid arginine, which is a precursor to nitric oxide, a key neurotransmitter in neural signaling. In the mouse inner ear, CPD mutations disrupted this arginine-nitric oxide pathway, leading to oxidative stress and death of sensory hair cells that are essential for detecting sound.
“CPD maintains arginine levels in hair cells to enable a rapid signaling cascade by generating nitric oxide,” Zhai explained. “Although CPD is expressed broadly in the nervous system, the delicate hair cells in the ear are particularly vulnerable to its loss.”
Model Organisms Point to Practical Treatments
Beyond mice, the team used fruit flies to model CPD-related effects. Flies with CPD mutations displayed behaviors consistent with ear damage, including hearing and balance challenges, reinforcing the relevance of this pathway to auditory function across species.
The researchers tested two therapeutic approaches aimed at the disrupted nitric oxide signaling: supplying arginine to compensate for its diminished production and administering sildenafil (Viagra), a drug known to stimulate a downstream pathway activated by nitric oxide. Both strategies improved cell survival in patient-derived cells and reduced hearing-loss behaviors in fruit flies, offering tangible avenues for clinical investigation.
Implications for Rare Disease Treatment and Beyond
“This work not only clarifies the cellular and molecular mechanisms behind this form of deafness but also highlights potential therapeutic options,” Zhai noted. “It exemplifies how repurposing FDA-approved drugs can accelerate treatments for rare diseases.”
The study also demonstrates the value of cross-species models, including fruit flies, in uncovering disease mechanisms and testing therapies. Such models provide a practical platform for exploring age-related sensory changes and other neurological conditions.
Next Steps and Future Questions
Looking ahead, the researchers plan to delve deeper into the nitric oxide signaling pathway within the inner ear’s sensory system and to assess CPD mutation prevalence in larger populations. Key questions include how common CPD variants are, whether they confer a broader risk for deafness or age-dependent hearing loss, and whether CPD-related pathways could underlie other sensory neuropathies.
The international collaboration includes researchers from the University of Miami; Ege University and Ankara University (Türkiye); Yüzüncü Yıl University and Memorial Şişli Hospital (Türkiye); Sanford University; University of Chicago; University of Iowa; and the University of Northampton, UK, with contributions from multiple institutions across the United States and Türkiye.
