Groundbreaking Discovery Links CPD Gene Mutations to Deafness
A collaborative team of scientists from the University of Chicago, the University of Miami, and several Turkish institutions has identified a mutation in the CPD gene that is closely linked to a rare form of congenital sensorineural hearing loss (SNHL). The findings, published in the Journal of Clinical Investigation, reveal not only a genetic cause for this deafness but also two potential therapeutic approaches that could mitigate the condition.
Lead author Rong Grace Zhai, PhD, Jack Miller Professor for the Study of Neurological Diseases at UChicago, emphasized the significance: this study not only uncovers a new gene mutation associated with deafness but also provides a tangible therapeutic target. While the research focused on a specific combination of CPD mutations observed in three unrelated Turkish families, the team notes that broader implications may emerge if single CPD mutations contribute to age-related hearing loss too.
The CPD-Related Mechanism: From Gene to Ear
The researchers began by analyzing a distinctive mutation pattern in CPD among families with congenital SNHL, a hereditary condition typically diagnosed in early childhood that results in permanent, irreversible hearing loss. Although devices like hearing aids and cochlear implants can help, there has been no medical treatment addressing the underlying disease itself.
A broader data search revealed additional individuals carrying CPD mutations with signs of early-onset hearing loss, suggesting a broader impact of this genetic pathway beyond the initial families. The team set out to understand how CPD mutations translate into hearing damage at the cellular level.
Arginine Depletion and Hair Cell Vulnerability
In a mouse model, the CPD gene was shown to encode an enzyme that helps produce the amino acid arginine, which then supports the production of nitric oxide — a key signaling molecule in the nervous system. The inner ear’s sensory cells, especially the delicate hair cells responsible for converting sound waves into neural signals, proved particularly susceptible when CPD function is compromised. The researchers found that CPD mutations disrupt the arginine-nitric oxide pathway, leading to oxidative stress and ultimately hair cell death.
“CPD maintains arginine levels in the hair cells to enable a rapid signaling cascade via nitric oxide,” Zhai explained. “While CPD is expressed in many cells, these hair cells are uniquely vulnerable to its loss, which helps explain the specific and devastating impact on hearing.”
Fruit Fly Model Informs Potential Treatments
To validate the findings and explore therapeutic avenues, the team used fruit flies as a model of CPD-related hearing damage. Flies with CPD mutations exhibited behavioral changes consistent with inner ear dysfunction, including impaired hearing and balance — reinforcing the translational relevance of the CPD-arginine-nitric oxide pathway.
The researchers then tested two strategies to counter the disrupted pathway. First, arginine supplements were used to replenish the deficit caused by CPD mutations. Second, sildenafil (Viagra), a drug known to stimulate the nitric oxide signaling pathway, was evaluated for its potential to mitigate the loss of hearing-related cell survival. In both cases, patient-derived cells showed improved viability, and fruit flies demonstrated reduced hearing-loss behaviors.
<h2 Toward Therapeutic Hope and Future Research
“These findings are meaningful not only for understanding a rare form of deafness but also for highlighting a potential therapeutic strategy that could be repurposed from existing FDA-approved drugs,” Zhai noted. The work exemplifies how a targeted genetic discovery can lead to practical treatments for rare diseases and may inform broader efforts to address age-related hearing decline in the future.
The team plans to deepen exploration of the nitric oxide signaling pathway within the inner ear and to assess CPD mutation prevalence in larger populations. Questions remain about how widespread CPD variants are and whether they confer susceptibility to other sensory neuropathies or age-related hearing loss individuals beyond the initial families studied.
Additional contributors include researchers from the University of Miami, Ege University, Ankara University, Yüzüncü Yıl University, Memorial Şişli Hospital, Sanford Research, the University of Iowa, and the University of Northampton, underscoring the international scope of this work and its potential to accelerate breakthroughs in genetic hearing science.
<h2 Implications for Patients and the Field
Ultimately, the discovery of a CPD mutation linked to congenital deafness, coupled with two actionable treatment approaches, represents a meaningful step toward translating genetic insights into patient care. As studies progress, clinicians may eventually have new options to slow or prevent hearing loss in individuals harboring CPD mutations, with potential ripple effects for related sensory disorders and age-related conditions.
