‘Holy grail’ find of protein directly tied to how our bodies (and other vertebrates) convert sound into hearing

Researchers have found a key protein associated with hearing function after decades of searching, with an aim towards identifying genetic mutations related to hearing loss and possible future medical treatments.

In a study published in August in Neuron, scientists say the discovery of the transmembrane channel-like protein 1 (TMC1) and its interaction with the pores along a mechanotransduction channel of the inner ear is seemingly a missing piece in understanding how our bodies convert sound information to hearing.

Mechanotransduction is any of the various mechanisms by which cells convert mechanical stimulus and electrochemical brain activity.

In hearing function, it represents the  the opening of ion channels of hair cells of the cochlea in the inner ear. TMC1 forms the central pore through which ions – like sodium, potassium and calcium – flow in response to sound. When sound enters the ear, it wiggles hair-like structures back and forth, causing the TMC1 channels to open and close.

Our ability to hear the world around us is incredibly fragile.

Even a single change in the 760 amino acids present in the TMC1 protein can lead to a dysfunctional protein and ultimately, deafness, according to Dr. Jeffrey Holt of Harvard Medical School and Boston Children’s Hospital.

Also, genetic mutations in over 100 genes identified so far can cause deafness because they disrupt transmission of sound information along the ion pathway. TMCs are a family of eight related proteins, two of which are present in the inner ear, Holt said in an interview with States of Life.

“We aim to identify why genetic mutations in those genes and proteins lead to hearing loss and to develop novel treatments for patients with hearing disorders,” Holt said.

Holt and colleagues experimented, creating 17 different TMC1 mutations in mice based on past research that established the concept that the protein formed the ion channel connection of the inner ear. TMC1 is a key molecule needed for conversion of sound into electrical signals, along with other necessary for transmission of electrical signals to the brain.

Without TMC1 we would all be deaf,” Holt said. “TMC1 is the key molecule at the interface between sound in the external world and our perception.  Sensitivity to sound of course allows us to understand and enjoy speech, music and a whole host of natural sounds that enhance quality of life.  In the natural world, sensitivity to sound offers a critical advantage for being able to hear predators and detect prey.  TMC1 and the sense of hearing likely evolved to provide strong survival advantages.”

So far, over 40 different genetic mutations in the protein that cause hearing loss.

“We are developing strategies to repair TMC1 in the ears of patients who are deaf due to TMC1 mutations,” Holt said. “The general strategies we are developing may also be useful for treating other forms of inherited human disease.”

Holt said future work, alongside with development of new treatment therapies for genetic hearing loss, would include understanding TMC1 at a molecular level and the structure of the molecule, along with the location and function of all 760 amino acids in the critical protein.

“We are also interested to understand the function of the other members of the TMC family: TMC2 – TMC8.  TMC2 is also present in the ear where it seems to play a key role in the sense of balance,” Holt said. “The function of the other TMC proteins is currently unknown.”

Dr. Jeffrey Holt is a neurophysiologist at the Department of Otolaryngology at BCH and HMS in Massachusetts. His lab is focused on identifying the genes and proteins required for the normal function of the sensory cells of the inner ear. The lab looks to identify why genetic mutations in those genes and proteins lead to hearing loss and to develop novel treatments for patients with hearing disorders.

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