Researchers have discovered a gene that links deafness to cell death in the inner ear in humans – creating new opportunities to prevent hearing loss.
A person’s hearing can be damaged by loud noise, aging, and even certain medications, with little recourse beyond a hearing aid or cochlear implant.
But now, UCSF scientists have made a breakthrough in understanding what happens in the inner ear during hearing loss, laying the groundwork for preventing deafness.
The research, published on December 22, 2023, in the Journal of Clinical Investigation Insight, links animal studies of hearing loss to a rare type of inherited deafness in humans. In both cases, mutations in the TMTC4 gene trigger a molecular domino effect known as the unfolded protein response (UPR), which leads to the death of hair cells in the inner ear.
Intriguingly, hearing loss from exposure to loud noise or drugs such as cisplatin, a common form of chemotherapy, also results from activation of the UPR in hair cells, suggesting that the UPR may underlie many different forms of deafness.
There are several drugs that block the UPR — and stop hearing loss — in lab animals. According to the researchers, the new findings strengthen the testing of these drugs in people at risk of hearing loss.
“Millions of American adults lose their hearing due to noise exposure or aging each year, but it’s been a mystery what went wrong,” said Dylan Chan, MD, PhD, co-senior author on the paper and director of the Children’s Communication Center. (CCC) at the UCSF Department of Otolaryngology. “We now have solid evidence that TMTC4 is a human deafness gene and that the UPR is a real target for preventing deafness.”
How hair cells in the ear self-destruct
In 2014, Elliott Sherr, MD, PhD, director of the UCSF Brain Development Research Program and co-senior author of the paper, noticed that several of his young patients with brain malformations all had mutations in TMTC4. But laboratory studies of this gene soon presented a conundrum.
“We expected that mice with TMTC4 mutations would have severe brain defects early on, like those pediatric patients, but to our surprise they appeared normal at first,” Sherr said. “But as these animals grew up, we saw that they didn’t startle in response to the loud noise. They had become deaf as they matured.”
Sherr worked with Chan, an inner ear specialist, to examine what was happening in the mice, which resembled an accelerated version of age-related hearing loss in humans. They showed that mutations in TMTC4 prompted hair cells in the ear to self-destruct, and loud noise did the same thing. In both cases, the hair cells were flooded with excess calcium, throwing off the balance of other cellular signals, including the UPR.
But they found there was a way to stop this. ISRIB, a drug developed at UCSF to block the self-destructive mechanism of the UPR in traumatic brain injury, prevented noise-exposed animals from becoming deaf.
The first human adult deafness gene
In 2020, scientists from South Korea, led by Bong Jik Kim, MD, PhD, linked Chan and Sherr’s 2018 findings to genetic mutations they found in two brothers who lost their hearing in their 20s. The mutations were in TMTC4 and matched what Chan and Sherr had seen in animals, although they were different from those in Sherr’s pediatric neurology patients.
“It’s rare that you connect mouse studies to humans so quickly,” Sherr said. “Thanks to our Korean partners, we could more easily demonstrate the relevance of our work to the many people who become deaf over time.”
Kim, an otolaryngologist at Chungnam National University College of Medicine (Korea), facilitated the transfer of cells from these patients to UCSF. Sherr and Chan tested these cells for UPR activity and found that, indeed, this flavor of the TMTC4 mutation activated the destructive UPR pathway in a human context.
When Chan and Sherr mutated TMTC4 only in hair cells in mice, the mice became deaf. When they mutated TMTC4 in cells from Korean family members who had not been deafened, and in human laboratory cell lines, the UPR drove the cells to self-destruct. TMTC4 was more than just a deafness gene in mice — it was a deafness gene in humans, too.
Translating a discovery to prevent deafness
Understanding TMTC4 mutations gives researchers a new way to study progressive deafness, which is critical for maintaining the health of the adult inner ear. The mutations mimic damage from noise, aging, or drugs like cisplatin.
The researchers envision a future where people who must take cisplatin, or who must be exposed to loud noises for their jobs, get a drug that dampens the UPR and protects hair cells from withering, preserving their hearing.
The science also suggests that the UPR could be targeted in other contexts where nerve cells are overwhelmed and dying, including diseases long considered incurable, such as Alzheimer’s or Lou Gehrig’s disease.
“If there’s some way we can prevent hair cells from dying, then we can prevent hearing loss,” Chan said.