New discovery ties CPD gene mutations to a rare form of congenital deafness
A collaborative international team of researchers has uncovered a gene mutation in CPD that plays a pivotal role in a rare form of congenital hearing loss. The study, led by scientists from the University of Chicago and the University of Miami, with partners in Turkiye, was published in the Journal of Clinical Investigation. The findings reveal that a gene typically associated with protein modification also influences the inner ear, suggesting potential therapeutic strategies for this debilitating condition.
Lead author Rong Grace Zhai, PhD, Jack Miller Professor for the Study of Neurological Diseases, emphasized the significance of the discovery: “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 research focused on a specific mutation combination in three Turkiye families with sensorineural hearing loss (SNHL), the team notes there could be broader implications for other forms of hearing loss, including age-related decline.
The CPD gene and the mechanism of deafness
Researchers began their investigation after identifying a unique constellation of CPD mutations in unrelated Turkiye families with congenital SNHL. Sensorineural hearing loss, diagnosed in early childhood, is usually permanent and currently lacks disease-modifying treatments. While hearing aids and cochlear implants can improve hearing, they do not address the underlying disease process.
To understand how CPD mutations affect the ear, the team explored how CPD normally supports neural signaling. The CPD gene encodes an enzyme that helps produce the amino acid arginine, which in turn leads to the production of nitric oxide — a key messenger in the nervous system. Using a mouse model that mirrors human inner-ear biology, the researchers found that CPD mutations disrupt this arginine–nitric oxide pathway, causing oxidative stress and death of the delicate hair cells responsible for detecting sound.
“CPD maintains the arginine level in hair cells to enable a rapid signaling cascade by generating nitric oxide,” Zhai explained. “Although CPD is expressed in many cells, the hair cells in the inner ear are particularly vulnerable to its loss.”
From fruit flies to potential therapies
The team extended their investigation to fruit flies, a common model for studying sensory and neurological disorders. Flies carrying CPD mutations exhibited behaviors consistent with inner-ear damage, including impaired hearing and balance issues, supporting the gene’s role in hearing biology.
Two therapeutic approaches showed promise in preclinical tests. First, arginine supplementation could compensate for the arginine deficit caused by CPD mutations, potentially restoring the signaling needed for hearing. Second, sildenafil (Viagra) was used to stimulate a downstream pathway affected by reduced nitric oxide, improving cell survival in patient-derived cells and reducing hearing-loss behaviors in fruit flies.
“What makes this really impactful is that we not only understand the cellular and molecular mechanism behind this form of deafness, but we also identify actionable therapeutic avenues,” said Zhai. The study also highlights the potential for repurposing FDA-approved drugs to treat rare diseases, expediting access to treatment for affected individuals.
Implications and next steps
The researchers plan further studies to map the nitric oxide signaling pathway in the inner ear more comprehensively and to assess how CPD variants affect broader populations. A key question is whether CPD variants might contribute to age-related hearing loss or other sensory neuropathies, a possibility Zhai notes with important public-health implications.
“How many people carry CPD variants, and do these variants confer risk for deafness or age-dependent hearing loss?” she asked. The team intends to explore prevalence and susceptibility in larger cohorts across multiple countries.
In addition to Zhai, authors include researchers from the University of Miami, Ege University and Ankara University in Turkiye, Yüzüncü Yıl University, Memorial Şişli Hospital, Sanford University, the University of Iowa, and the University of Northampton. This work exemplifies international collaboration in deciphering complex genetic diseases and advancing potential therapies for congenital deafness.
