Of mice and men: Deaf mouse leads scientists to new human hearing loss gene

In a powerful demonstration of how animal research can help humans, a pair of scientific teams is reporting the discovery of defects in a deafness gene in mice that led to the identification of similar genetic defects in people with hearing loss.

The findings, published in two new papers, may eventually lead to a screening test and therapy for families affected by one type of inherited hearing loss.

The discoveries also bring scientists closer to understanding the intricate choreography of genes and proteins involved in the normal development of human hearing — and the tiny missteps that can destroy hearing even before a baby is born.

The discovery of the human deafness gene, called TMIE, is reported in the September issue of the American Journal of Human Genetics. The finding relied on the discovery of a mouse gene, Tmie, first reported in the August issue of Human Molecular Genetics.

The mouse studies were conducted at the Kresge Hearing Research Institute, part of the University of Michigan Health System, using two deaf strains of mice from the Jackson Laboratory in Maine. One mouse strain, called ’spinner’ because their inner ear problems cause them to spin madly in circles, was found in the 1960s. The other strain used in the study was identified more recently.

At the U-M, senior author David Kohrman, Ph.D., and his colleagues have worked for three years to pinpoint the Tmie gene, guided by earlier studies on spinner mice that gave them a general location for searching.

Once they found the gene, and the mutations in it that caused deafness in the two strains of mice, they explored how those mutations affect the structure and function of the inner ear, leading to deafness. They think the mutations alter the tiny hair-like stereocilia that coat the “hair cells” of the inner ear and are crucial to hearing.

Recently, Kohrman shared this knowledge with colleagues at the University of Iowa and at the National Institute on Deafness and Other Communication Disorders, of the National Institutes of Health.

For years, the Iowa and NIH teams have studied several Indian and Pakistani families with a history of inherited hearing loss. They had found the general location of the gene involved in the families’ hearing problems, but specific information from the U-M mouse study helped them zero in on it.

Using DNA segments made by Kohrman’s team to “search” for similar stretches of DNA in tissue samples from the families, the groups at Iowa and NIH checked for defects in the human TMIE gene. They found three mutations in a day and a half, then found two more — each causing hearing loss in one of five different families.

“This shows how useful mice are as models for the human ear, and how powerful gene mapping and a classical genetic approach can be,” says Kohrman, an assistant professor of otolaryngology at the U-M Medical School. “This gives us an inroad to open up other areas of the genome involved in deafness.”

The Iowa-NIH team agrees. “We still have much to learn about TMIE, but it’s clear that it plays a critical role in the auditory system — one that has stayed much the same since mouse ancestors and human ancestors branched off the evolutionary tree,” says Edward R. Wilcox, Ph.D., a researcher in the NIDCD Laboratory of Molecular Genetics and senior author of the human gene paper.

“It’s a really exciting time for deafness research, and this is another advance in putting together a piece of the whole puzzle,” says Richard J.H. Smith, M.D., the Sterba Hearing Research Professor at the University of Iowa. “This shows what can happen when labs work together, because having the mouse gene definitely sped things up for those of us searching for the human gene.”

Kohrman credits the public mouse genome database for speeding his team’s research. Both TMIE and Tmie are located on a stretch of DNA that is similar in humans and mice — a stretch that has been sequenced by both the mouse and human genome projects.

The ready availability of DNA sequences is making it easier for scientists to get to the bottom of inherited deafness, which accounts for about half of all hearing loss in people under 30. Scientists estimate that half of all inherited hearing loss cases are due to mutations in a single gene called connexin 26, found in 1997.

But researchers are still piecing together the other genes involved in the rest of the genetic deafness cases. The new TMIE gene will be added to a list of more than 25 others.

No matter how many people actually carry TMIE mutations, the finding in both the human families and the mice will help researchers continue to study the impact of genetics on hearing. It’s already allowing them to test ideas for screening for, and even correcting, mutations.

Now, Kohrman and his team are working to develop a transgenic mouse that carries a normal Tmie gene, so they can test approaches for turning the gene on and off. They also hope to build a virus-based “vector” that will allow them to insert a normal Tmie gene into mice that carry a mutated version of the gene, in an attempt to correct the problem.

Kohrman’s colleague Yehoash Raphael, Ph.D., M.Sc., who directs Kresge’s Otopathology Laboratory, will continue to aid the reseach using an electron microscope to see the alterations that Tmie mutations cause in the stereocilia of the inner ear’s hair cells. By studying the cells at different stages of mouse development, and comparing their growth with the activation of the Tmie gene that occurs at the same time, they may learn exactly when and how Tmie works.

“Sensory cells are a small proportion of all the cells in the ear, but they’re some of the most important,” says Kohrman. “Anything we can do to find out how they develop will be significant.”

Besides Kohrman and Raphael, the mouse gene team includes U-M senior associate research scientist David F. Dolan, Ph.D.; U-M research associates Lisa Beyer, Gary Dootz and lead author Kristina Mitchem, M.S.; former U-M research assistant Ellen Hibbard; and Ken Bosom and Kenneth R. Johnson of the Jackson Laboratory.