New Evidence Spots CPD Gene Mutations as a Driver of Congenital Hearing Loss
A global team of researchers has identified mutations in the CPD gene as a key factor in a rare form of congenital hearing loss. The study, conducted by scientists from the University of Chicago, the University of Miami, and several Turkish institutions, was published in the Journal of Clinical Investigation. The findings illuminate how a gene classically linked to protein modification can also disrupt inner-ear function, and they point to two potential therapeutic strategies to mitigate the condition.
How CPD Mutations Affect the Inner Ear
The researchers began by examining a distinctive mutation pattern found in three unrelated Turkish families with sensorineural hearing loss (SNHL), a hereditary condition diagnosed in early childhood that often results in permanent deafness. Intriguingly, analysis of broader genetic databases revealed that other individuals carrying CPD mutations also show signs of early onset hearing loss, suggesting a wider relevance beyond the initial families.
Arginine Deficiency and Hair-Cell Vulnerability
In a series of experiments using a mouse model whose inner ear resembles the human cochlea, the team traced how CPD normally helps maintain arginine levels. Arginine is a precursor to nitric oxide, a critical signaling molecule in neural communication. When CPD is mutated, the pathway that sustains arginine and, consequently, nitric oxide is disrupted. The result is oxidative stress and targeted death of the sensory hair cells in the cochlea—the delicate structures responsible for translating sound waves into neural signals.
“CPD keeps arginine at the level needed for a rapid signaling cascade via nitric oxide,” explained lead author Dr. Rong Grace Zhai. “While CPD is expressed broadly, the inner-ear hair cells appear especially vulnerable to its loss.”
From Model Organisms to Potential Treatments
Beyond mice, the team used a fruit fly model to study CPD-related changes. Flies with CPD mutations exhibited behaviors consistent with hearing and balance impairments, reinforcing the relevance of CPD to sensory function across species.
Crucially, the researchers tested two therapeutic approaches aimed at correcting the disrupted nitric oxide pathway:
- Arginine supplementation to compensate for reduced arginine production
- Pharmacological stimulation of the pathway using sildenafil (Viagra), which promotes nitric oxide signaling
In patient-derived cells, both strategies improved cell survival. In fruit flies, they reduced behaviors associated with hearing loss, suggesting that these approaches could translate into real-world therapies for affected individuals.
Implications for Rare Diseases and Beyond
“This work is exciting not only because we’ve identified a new gene mutation linked to deafness, but because we’ve pinpointed a therapeutic target that can actually mitigate the condition,” said Zhai. The study also highlights how repurposing FDA-approved drugs can accelerate treatment development for rare diseases.
Researchers note the broader significance of the work: although focused on a compounded CPD mutation, there may be implications for single-variant CPD alterations that contribute to age-related hearing loss or other sensory neuropathies. The team plans further studies into the nitric oxide signaling pathway and aims to determine how prevalent CPD variants are in larger populations.
Next Steps and Future Questions
The researchers intend to explore how CPD-related arginine and nitric oxide dynamics operate within the inner ear’s sensory system and to evaluate CPD mutation frequencies in diverse cohorts. They also want to investigate whether CPD variants can serve as a broader risk factor for various forms of sensory neuropathy and age-associated hearing decline.
With these findings, the study points to a hopeful path forward for individuals with this rare congenital hearing loss and opens doors to broader insights into how metabolic pathways influence sensory health.
