Mutations in a gene known as CPD play a crucial role in a rare form of congenital hearing loss, an international team of researchers has discovered. Scientists from the University of Chicago, the University of Miami, and several institutions in Turkiye published their findings in the Journal of Clinical Investigation, showing that the mechanism by which the gene, typically associated with altering proteins, affects the inner ear as well. The team also identified two potential approaches to treating the condition.

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."

Rong Grace Zhai, PhD, lead author, Jack Miller Professor for the Study of Neurological Diseases of Neurology at UChicago

Although the study focused on individuals with a rare combination of mutations to the CPD gene, there could be broader implications if single mutations are linked to age-related hearing loss, she added.

The link between CPD and hearing loss

Researchers initially zeroed in on the CPD gene after identifying a distinct combination of mutations in three unrelated families from Turkiye with a congenital form of deafness known as sensorineural hearing loss, or SNHL.

The condition, which is hereditary and usually diagnosed in early childhood, causes permanent hearing loss and is thought to be irreversible. Although hearing may be improved with hearing aids and cochlear implants, there is currently no medical treatment available for the condition itself.

When the scientists analyzed a genetic database, they found that other people with CPD mutations also showed signs of early onset hearing loss.

Sensory cells vulnerable to arginine depletion

The researchers conducted a mouse study to gain a deeper understanding of how the CPD gene influences hearing. Normally, the CPD gene encodes an enzyme that produces the amino acid arginine, which in turn produces nitric oxide, an important neurotransmitter that helps send signals through the nervous system. By studying the mouse inner ear, which is similar to humans, the scientists found that mutations in the CPD gene disrupted this pathway, leading to oxidative stress and cell death in the ear's sensory cells, especially in the delicate hairs that detect sound waves.

"It turns out that CPD maintains the level of arginine in the hair cells to allow a quick signaling cascade by generating nitric oxide," Zhai explained. "And that's why, although it's expressed ubiquitously in other cells throughout the nervous system, these hair cells in particular are more sensitive or vulnerable to the loss of CPD."

Fruit fly model shows treatment benefits

The team also used fruit flies as a model to study the effects of CPD changes. They found that fruit flies with the CPD mutations showed behavioral changes consistent with inner ear damage, like hearing loss and balance problems.

Finally, researchers tested two approaches to treating the disrupted pathway: arginine supplements to compensate for the arginine lost due to the CPD mutation, and the drug sildenafil (Viagra), which they knew would stimulate one of the pathways affected by the loss of nitric oxide. Both approaches improved cell survival in patient cells and reduced hearing-loss behaviors in fruit flies.

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

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

A rare condition with wider implications

Next, the researchers plan to conduct additional studies to gain a deeper understanding of the nitric oxide signaling pathway and its role in the sensory system of the inner ear. They also want to study the prevalence of CPD mutations in larger populations.

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