Researchers Identify Gene Linked to Progressive Hearing Loss from Noise and Aging

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In the study published January 24 in the early online issue of the Proceedings of the National Academy of Sciences (PNAS), Liu, associate professor and Director of Research in the Department of Otolaryngology, and his team found that a mutation in P2X2 increases the susceptibility to both age- and noise-related hearing loss associated with DFNA41, a form of progressive nonsyndromic hearing loss that begins early in life, often in adolescence, and progresses with age. Generally accompanied by high frequency tinnitus, high-pitched ringing in the ears, the hearing loss ranges from severe to profound over decades.

“Age-related hearing loss and noise-induced hearing loss are two of the most common morbidities in the world, affecting more than 500 million people, but virtually nothing is known of the genetics that underlies them,” said Liu, also an associate member of The John P. Hussman Institute for Human Genomics, which collaborated on the study. “Our identification of the P2X2 gene as a factor in progressive hearing loss is the first step in understanding the genetic causes of both noise-induced and age-induced hearing loss.”

Funded by the NIH’s National Institute on Deafness and Other Communication Disorders (NIDCD), the researchers specifically discovered that the P2X2 mutation found in DFNA41 results in defects in sensory hair cells in the inner ear, which eventually lead to ongoing hearing loss. The study establishes, at the cellular and molecular levels, that the function of this ion channel, previously known to be involved in sensory signaling and pain, has a major impact on noise-induced and age-related hearing loss.

“This is groundbreaking work,” said Miller School Dean Pascal J. Goldschmidt, M.D., who is also Senior Vice President for Medical Affairs. “Not only does it give scientists a way to develop a targeted treatment for progressive hearing loss in humans with DFNA41, it also may open doors to the treatment of noise-induced and age-related hearing loss in the wider population.”

Noting that DFNA41is the first example of a human disease caused by a mutation in the P2X2 gene, Fred Telischi, M.D., Professor and Chair of Otolaryngology, said, “The findings emphasize the importance of a genetic approach for uncovering hearing impairment related to noise exposure and aging.”

For the PNAS study, “Mutation of the ATP-gated P2X2 receptor leads to progressive hearing loss and increased susceptibility to noise,” the researchers identified two Chinese families with DFNA41 and found that members of those families who carried the mutation and were exposed to noise as young adults had significantly poorer hearing at high frequencies than those without the mutation. Those without it had no hearing loss when exposed to noise.

Then the investigators manipulated human cells and mice to determine the role of the P2X2 in progressive hearing loss. They tested the effect of exposure to moderate noise — levels within legally permissible limits for long-term human exposure — on a group of normal wild mice and a group that had the gene deleted. They found that, when exposed to moderate continuous noise from birth to young adulthood (15 weeks), both the wild and knockout mice experienced hearing loss at the frequency (kHz) of exposure. However, in the knockout mice, hearing was significantly impacted not only at the exposed frequency, but at higher frequencies — that is, across the entire hearing spectrum, which indicates noise as the cause for these losses.

Other Miller School researchers on the study included first author Denise Yan, Ph.D., research assistant professor of otolaryngology; Asli Sirmaci, Ph.D., a former post-doc at the Hussman Institute; Lilin Du, research associate, and M’hamed Grati, assistant scientist, both in the Department of Otolaryngology; Susan Halloran Blanton, Ph.D., Executive Director of the Hussman Institute and associate professor of human genetics; and Mustafa Tekin, M.D., associate professor of human genetics. International collaborators included clinical colleagues in China. Also contributing were Mary-Claire King and Tom Walsh at the University of Washington; Hongbo Zhao at the University of Kentucky; Bechara Kachar, M.D., chief of the NIDCD laboratory of cell structure and dynamics; Allen Ryan at the University of California San Diego; Zheng-yi Chen of Harvard Medical School; and Gary Housley and Peter Thorne of the Universities of New South Wales and Auckland, respectively.

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