Ulrich Mueller, PhD, The Scripps Research Institute

Ulrich Mueller, PhD, The Scripps Research Institute

A mutation in a gene called Tmie can cause deafness from birth, say scientists at The Scripps Research Institute (TSRI). According to a study, published in the November 20 edition of the journal Neuron, the Tmie gene is essential to hearing, and the new findings about the gene mutation help uncover a cause of deafness and suggest new avenues for therapies.

The TSRI researchers report they were able to reintroduce the gene in mice and restore the process underpinning hearing.

“This raises hopes that we could, in principle, use gene-therapy approaches to restore function in hair cells and thus develop new treatment options for hearing loss,” said Ulrich Müller, PhD, senior author of the new study, chair of the Department of Molecular and Cellular Neuroscience, and director of the Dorris Neuroscience Center at TSRI.

How the Tmie gene mutation causes hearing loss.

In describing the ear, scientists often describe it as a complex machine that converts mechanical sound waves into electric signals for the brain to process. When a sound wave enters the ear, the uneven ends of the inner ear’s hair cells (stereocilia) are pushed back like blades of grass bent by a heavy wind. The movement causes tension in the strings of proteins (tip links) connecting the stereocilia, which sends a signal to the brain through ion channels that run through the tips of the hair cell bundles.

This process of converting mechanical force into electrical activity, called mechanotransduction, still poses many mysteries. Researchers have been mystified about how signals are passed along the tip links to the ion channels, which shape electrical signals.

To track down this unknown component, researchers in the study at TSRI reportedly built a library of thousands of genes with the potential to affect mechanotransduction. The research team spent 6 months screening the genes to see if the proteins the genes produced interacted with tip link proteins. Eventually, the team found a gene, Tmie, whose protein, TMIE, interacts with tip link proteins and connects the tip links to a piece of machinery near the ion channel.

This new discovery answers a long-standing question in neuroscience. Scientists have long known that mutations in the Tmie gene could cause deafness—but they weren’t sure how.

Once the TRSI researchers found that Tmie plays a role bridging the tip links and ion channels, they bred a population of “knock-out mice” that lacked the gene. They examined the hair cells of the mice with electrophysiological techniques and found that without Tmie, no electrical signal could be evoked in hair cells after stimulation.

“The mechanotransduction current is gone; the mouse is totally deaf,” explained Bo Zhao, a research associate in the Müller lab and first author of the new paper.

In a second experiment, the researchers reintroduced Tmie to mice that had been deaf since birth and found the electrical signals were restored. Müller reported that the next challenge is to find out how the individual components of the complex mechanotransduction system form in hair cells.

“We would also like to understand the biophysical principles by which these proteins convert mechanical signals into electrical signals,” said Müller.


Source: The Scripps Research Institute