Cincinnati -- A team of biologists has found that mice lacking the gene for a key thyroid hormone receptor suffer severe deafness, even though they appear and behave normally in all other respects.
The team, which includes Professor Lawrence Erway of the University of Cincinnati and Assistant Professor Douglas Forrest of the Mount Sinai School of Medicine in New York City, reports in the current issue of Nature Genetics that thyroid hormone receptor beta is essential for normal hearing.
Forrest developed the knockout mice in collaboration with Lily Ng and Tom Curran, while they were at the now-defunct Roche Institute of Molecular Biology in Nutley, New Jersey. Curran is now at the St. Jude Children's Research Hospital in Memphis, Tennessee.
At first, the only detectable difference was the unusually high levels of thyroid hormone produced by adult mice in which the receptor gene was knocked out. However, Forrest was intrigued by the idea that the receptor may control the development of hearing, because deafness has long been linked with human infants born with severe thyroid diseases.
Erway, who has spent years studying the genetics of hearing loss in a variety of mouse strains, then tested young knockout mice and discovered they were deaf.
"They appear not to have normal development of hearing from the youngest age we tested which is about 18 days of age," said Erway.
Testing hearing in mice requires a special procedure known as auditory-evoked brainstem response or ABR. A series of clicks and pure tones are used to stimulate the auditory system, then electrodes measure the response in the brain.
Erway's results showed a clear difference between mice with one copy of the receptor gene (heterozygotes) and those with both copies of the gene knocked out (homozygotes). The heterozygotes responded at much lower decibel levels, closely matching the results from normal-hearing control mice. Erway said the homozygotes barely responded at even the loudest noise levels.
"The ABR threshold is very much elevated, upwards to 100 decibels. At that point, you can certainly say the mice are deaf. They're incapable of hearing anything."
Forrest believes this knockout strain will provide a good model for scientists studying deafness in humans. "We've shown very specifically that the loss of this gene causes profound deafness. So very likely, it's a loss of this receptor that causes some genetic forms of human deafness."
The knockouts can also be used to study the early development of the auditory system. "Thyroid hormone receptor-beta is a transcription factor, so it has the potential to be a key trigger point in the development of the auditory system," explained Forrest.
The big mystery right now is exactly how the lack of the receptor causes hearing loss. Neuroanatomist Richard Altschuler of the Kresge Hearing Research Institute at the University of Michigan could find no obvious defects in the cochlea, the critical portion of the inner ear where sound waves are converted into nerve signals and the area where the thyroid receptor gene is known to be expressed.
A follow-up study will include a detailed look at the cilia on the so-called "hair cells" of the cochlea, the cells which actually respond to the pressure of the sound waves. Erway says an electron micrograph might show changes which weren't apparent under the light microscope.
The research was supported in part by the National Institutes of Health.