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Scripps Research Scientists Find Deafness Gene s Function

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A group of scientists at The Scripps Research Institute, at the University of California in San Diego, and at the Oregon Hearing Research Center and Vollum Institute at Oregon Health & Science University have discovered a molecule involved in mediating the sense of hearing.

In a paper slated to appear in an upcoming issue of the journal Nature, the team reported that the cadherin 23 protein is part of a complex of proteins called “tip links” that are on hair cells in the inner ear. These hair cells are involved in mechanotransduction, a phenomenon in hearing in which sound waves are transduced into electrochemical signals and communicated to the brain. The tip link is believed to play a central role in this conversion of physical cues into electrochemical signals.

“In humans, there are mutations in [the gene] cadherin 23 that cause deafness as well as Usher syndrome, the leading cause of deaf-blindness,” Ulrich Mueller, of the department of Cell Biology at The Scripps Research Institute and a member of the Institute for Childhood and Neglected Diseases, said in a statement.

A parallel study led by Mueller’s collaborator Teresa Nicolson and colleagues at the Oregon Hearing Research Center and Vollum Institute corroborated Mueller’s results by showing that when the cadherin 23 gene is deleted in mutant zebrafish, tip links never form.

Both studies explain how the cadherin 23 gene is a direct cause of certain types of deafness and suggest a potential therapeutic target for treating deafness.

In Usher syndrome and some other “sensory neuronal” diseases that cause deafness, the hair cells in the cochlea are unable to maintain the symmetric arrays of stereocilia.

The tip link molecular complex was discovered a few decades ago in the stereocilia. These tip links connect the tips of stereocilia and are also thought to be important for the transmission of physical force to mechanically gated ion channels.

For Mueller, who studies topics at the intersection of neuroscience and genetics, tip links appeared to be a key in understanding and addressing Usher syndrome, and the way forward was to identify the proteins in the tip links.

Mueller and his colleagues reasoned that one of the molecules in tip links would be the type of molecule that mediates cell-cell interactions and keeps the stereocilia bundled. They also had evidence from studies by colleagues that these molecules were dependent upon calcium for their action.

With these facts in mind, they scanned all known proteins in the human and mouse genome to see which fit the profile, and they were able to focus in on two gene families — the cadherins and the integrins.

The scientists then looked at the relative sizes of cadherins and integrins. One particular cadherin protein, cadherin 23, appeared to be the right size. Combined with the fact that mutations in the cadherin 23 gene are associated with deafness and deaf-blindness, it became the prime suspect in their search.

In their Nature article, Mueller and his colleagues showed that the protein cadherin 23 is expressed in the right place in the hair cell to be part of the tip link; that it has the correct biochemistry; and that it seems to be responsible for opening the ion channels. They also showed that cadherin 23 protein forms a complex with another protein called myosin 1c, which helps to close the channel once it is open.

They predicted that the two proteins form a complex with the unknown ion channels, and they are now trying to identify other molecular components of the tip links.

Interestingly, age-related hearing loss in humans may also be related to problems in the tip links and defects in mechanotransduction. Point mutations in the cadherin 23 protein have already been associated with age-related hearing loss in mice. It will therefore be important to analyze the extent to which Cadherin 23 function may be affected in humans that suffer from age related hearing impairment.

— KL

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