Scientists have discovered a hidden genetic mutation that causes deafness, and a way to fix it

“This study is exciting because we have found a new genetic mutation associated with deafness, and more importantly, we have a therapeutic target that can actually alleviate this condition,” said lead author Rong Grace Zhai, Ph.D., the Jack Miller Professor for the Study of Neurodegenerative Diseases in Neuroscience at the University of Chicago. She added that although the study focused on individuals with a rare combination of mutations in the CPD gene, there may be broader implications if individual mutations are associated with age-related hearing loss.

The relationship between CPD and hearing loss

Researchers began investigating CPD after identifying an unusual cluster of mutations in three Turkish families unrelated to sensorineural hearing loss (SNHL), a congenital and hereditary condition that causes permanent deafness.

SNHL is usually diagnosed in early childhood and has long been considered untreatable. Hearing aids and cochlear implants can help improve sound perception, but there is no direct medical treatment to repair the underlying damage.

When the scientists expanded their search through genetic databases, they discovered that individuals with other CPD mutations also showed signs of early hearing loss, strengthening the relationship between this gene and auditory function.

How CPD protects sensory cells

To understand how CPD affects hearing, the team conducted experiments using mice. The CPD gene normally produces an enzyme responsible for producing the amino acid arginine, which then helps create nitric oxide, a key neurotransmitter involved in nerve signaling. In the inner ear, mutations in CPD disrupted this process, leading to oxidative stress and death of sensitive sensory hair cells that detect sound vibrations.

“It turns out that CPD maintains the level of arginine in hair cells to allow a rapid signaling cascade by generating nitric oxide,” Zhai explained. “For this reason, although they are ubiquitously expressed in other cells throughout the nervous system, these hair cells in particular are more sensitive or susceptible to CPD loss.”

Fruit fly experiments reveal potential treatments

The researchers also used fruit flies as a model to explore how CPD mutations affect hearing. Flies carrying the defective gene showed behaviors consistent with an inner ear defect, such as hearing loss and balance problems.

To test potential treatments, scientists tried two methods. One was to provide arginine supplements to replace what was lost due to the genetic defect. The other method was to use sildenafil (Viagra), a drug known to stimulate one of the signaling pathways that had been disrupted by low nitric oxide. Both treatments improved cell viability in patient-derived cells and reduced symptoms of hearing loss in fruit flies.

“What makes this really impactful is that not only do we understand the underlying cellular and molecular mechanism of this type of deafness, but we have also found a promising therapeutic avenue for these patients,” Zhai said. “It is a good example of our efforts to repurpose FDA-approved drugs to treat rare diseases.”

The study also demonstrates the value of fruit fly models for studying neurological diseases, including age-related conditions, Zhai noted. “It gives us the ability to not only understand the pathology of the disease, but also to identify therapeutic approaches,” she said.

Expanding the scope of research to include broader population segments

The researchers plan to continue studying how nitric oxide signals work in the sensory system of the inner ear. They also aim to investigate how common CPD mutations are in large populations and whether they may contribute to other forms of hearing loss.

“How many people carry variants in this gene and is there an age-dependent susceptibility to deafness or hearing loss?” She said. “In other words, is this a risk factor for other types of sensory neuropathy?”

The study involved collaborators from multiple institutions, including the University of Miami, Ece University, Ankara University, Yuzuncu Yale University, Sisli Memorial Hospital, University of Iowa, and University of Northampton (UK).