New Insights into a Rare Cause of Congenital Hearing Loss
A multinational team of researchers has identified mutations in a gene known as CPD as a key factor in a rare form of congenital hearing loss. Published in the Journal of Clinical Investigation, the study from scientists at the University of Chicago, the University of Miami, and partnering Turkiye institutions shows how CPD, traditionally linked to protein modification, also disrupts a critical pathway in the inner ear. The finding not only clarifies disease mechanisms but also points to two potential treatment strategies that could mitigate the condition.
From Protein Processing to Inner-Ear Biology
The CPD gene encodes an enzyme involved in producing the amino acid arginine, which in turn drives the synthesis of nitric oxide, a neurotransmitter essential for signaling in the nervous system. In the context of the inner ear, the researchers discovered that CPD mutations disturb this pathway, causing oxidative stress and death of sensory hair cells—the very cells responsible for translating sound into neural signals. Lead author Rong Grace Zhai, PhD, emphasizes that the hair cells in the inner ear are especially vulnerable to CPD disruption, even though CPD is expressed broadly elsewhere in the nervous system.
Tracing the Genetic Footprint
Initially, the team focused on a distinctive combination of CPD mutations found in three unrelated Turkiye families with congenital sensorineural hearing loss (SNHL). SNHL is hereditary and usually diagnosed in early childhood, often leading to irreversible hearing impairment. While devices such as hearing aids or cochlear implants can improve function, there has been no disease-specific medical treatment. By analyzing broader genetic databases, the researchers found additional individuals carrying CPD mutations who exhibited early-onset hearing loss, suggesting a broader role for CPD in auditory health.
Model Systems Shed Light on Mechanisms and Potential Therapies
To explore how CPD mutations affect hearing, the scientists used a two-pronged modeling approach: a mouse model and a fruit fly model. In mice, CPD mutation disrupted arginine production and nitric oxide signaling in the inner ear, precipitating oxidative stress and hair-cell death. This provided a clear cellular mechanism linking CPD to hearing loss. In fruit flies, CPD mutations produced behavioral changes consistent with inner-ear dysfunction, such as hearing deficits and balance issues, reinforcing the relevance of CPD-related pathways across species.
Two Potential Therapeutic Avenues
The researchers then tested two strategies aimed at restoring the disrupted pathway. The first involved arginine supplementation to compensate for reduced arginine production caused by CPD mutations. The second used sildenafil (Viagra), a drug known to stimulate pathways downstream of nitric oxide signaling. Both approaches improved cell survival in patient-derived cells and reduced hearing-loss behaviors in the fruit fly model, highlighting the potential for repurposing FDA-approved drugs to treat this rare deafness.
Broader Implications and Future Directions
“What makes this really impactful is not only understanding the cellular and molecular mechanism behind this form of deafness, but also identifying a therapeutic avenue that could directly help patients,” Zhai says. The study also underscores the value of simple model organisms in unraveling complex neurological diseases and exploring treatments, including those relevant to age-related conditions.
Looking ahead, the team plans to dissect the nitric oxide signaling pathway more fully and determine how widespread CPD variants are in larger populations. Key questions include whether CPD variants confer susceptibility to deafness or age-related hearing loss and, more broadly, whether CPD variants act as risk factors for other sensory neuropathies. The work represents a hopeful step toward targeted therapies for a rare but impactful condition.
Conclusion: A New Therapeutic Target for Deafness
By linking CPD mutations to inner-ear biology and demonstrating two viable treatment approaches, this research offers a roadmap for translating genetic insights into clinical options. If confirmed in larger studies, arginine-based supplementation and nitric oxide–modulating therapy could become meaningful interventions for patients with CPD-related hearing loss and potentially related sensory conditions.
