Found: New Gene for Lost Hearing

Marci Lesperance Photo: Marcia Ledford

An international research team led by University of Michigan Medical School scientists Marci Lesperance, M.D., and Margit Burmeister, Ph.D., has identified a gene responsible for an unusual type of hearing loss called low frequency sensorineural hearing loss.

U-M researchers discovered that children who inherit one copy of the mutated gene called WFS1 gradually lose their ability to hear low-frequency sounds. The hearing loss becomes more severe over time, and eventually hearing aids are required. Patients with different types of mutations affecting both copies of the gene develop Wolfram Syndrome 1 — a rare, devastating condition involving juvenile diabetes, optic atrophy, and often deafness and psychiatric illness.

The wider significance of this discovery is that mutations in this gene may be a common cause of low-frequency hearing loss in the general population, even in those who may be unaware that their hearing loss could be inherited.

Results of the study appeared in the October 22, 2001, issue of Human Molecular Genetics, published online November 20 at http://hmg.oupjournals.org.

“Discovering a new gene and its related protein gives scientists another piece of information to increase their understanding of inner ear development and function,” says Lesperance, an assistant professor of otolaryngology in the U-M Medical School. “These proteins are produced in tiny amounts in the inner ear or cochlea — an area that is inaccessible for tissue sampling and difficult to study.”

Lesperance’s research team worked closely with Burmeister and Irina Bespalova, Ph.D., of U-M’s Mental Health Research Institute, as well as with collaborators at the University of Antwerp and Rockefeller University, to identify mutations in six families from the U.S. and The Netherlands with a history of low frequency hearing loss.

“Affected individuals in each family had one of five minor variations called missense mutations in their WFS1 gene,” says Burmeister, an associate professor of psychiatry and of human genetics in the Medical School and senior associate research scientist in the Mental Health Research Institute. “Even though these mutations changed just one amino acid in the string of 890 amino acids that make up the protein, it was enough to produce progressive hearing loss.”

One of the most challenging parts of the study was locating families with this type of hearing loss. “People who can’t hear low-frequency sounds may not be aware of it, because their ability to understand speech isn’t affected,” adds Lesperance. “So it’s possible that this type of hearing loss is more common than we think. Many people in these families did not know about their hearing loss until they went to a rock concert and temporarily lost hearing in the high frequencies, as well.”

Lesperance believes there may be a connection between mutations in WFS1 and the more common form of progressive sensorineural hearing loss involving high-frequency sounds like human speech. While family members with WFS1 mutations had low-frequency hearing loss as children, they often lost the ability to hear high-frequency sound as they got older. “High-frequency hearing loss is caused by aging, noise exposure or drug toxicity, but mutations in WFS1 might make people more susceptible,” she says.

Lesperance also wants to explore possible involvement of the WFS1 gene in Meniere’s Disease — a common, disabling condition that combines periodic attacks of low-frequency hearing loss with severe vertigo and tinnitus, or ringing in the ears.

The study was funded by the National Institutes of Health, the U-M Biomedical Research Council, the University of Antwerp and the Flemish FWO, the Starr Center for Human Genetics and the American Hearing Research Foundation.

Collaborators from the University of Michigan included Irina N. Bespalova, Ph.D., former research investigator, now an assistant professor of psychiatry at Mount Sinai School of Medicine; David J. Brown, M.D., house officer in otolaryngology; Ayse E. Erson, a graduate student in human genetics; Purnima Kurnool, former research associate; and Theru A. Sivakumaran, Ph.D., research fellow in otolaryngology.

—Sally Pobojewski

For more information on inherited hearing loss and Lesperance’s research, visit:
www.med.umich.edu/childhearinginfo
http://otosclerosis.khri.med.umich.edu
www.khri.med.umich.edu/research/lesperance_lab/index.htm