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Scripps Research Scientists Find Deafness Gene's Function

La Jolla, CA, March 26, 2004 - A group of scientists at The Scripps Research Institute, at the University of California, San Diego, and at the Oregon Hearing Research Center and Vollum Institute at Oregon Health & Science University have discovered a key molecule that is part of the machinery that mediates the sense of hearing.

In a paper that will appear in an upcoming issue of the journal Nature, the team reports that a protein called cadherin 23 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 the physiological process called mechanotransduction, a phenomenon in hearing in which physical cues (sound waves) are transduced into electrochemical signals and communicated to the brain. The tip link is believed to have a central function in the 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," says Associate Professor Ulrich Mueller, Ph.D., who is in the Department of Cell Biology at The Scripps Research Institute and is a member of Scripps Research's Institute for Childhood and Neglected Diseases.

A parallel study led by Mueller's collaborator Teresa Nicolson, Ph.D., and her 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.

The Physiology of Hearing and Deafness

Childhood and age-related hearing impairment is a major issue in our society. According to the National Institute on Deafness an Other Communication Disorders, one in three people older than 60 and about half of all people over 75 suffer some form of hearing loss. And about four out of every 100,000 babies born in the United States have Usher syndrome, the major cause of deaf-blindness.

Hearing is a classic example of a phenomenon called mechanotransduction, a process that is important not only for hearing, but also for a number of other bodily functions, such as the pereception of touch. It is a complicated process whereby spatial and physical cues are transduced into electrical signals that run along nerve fibers to areas in the brain where they are interpreted.

Sound starts as waves of mechanical vibrations that travel through the air from their source to a person's ear through the compression of air molecules. When these vibrational waves hit a person's outer ear, they go down the ear canal into the middle ear and strike the ear drum. The vibrating ear drum moves a set of delicate bones that communicate the vibrations to a fluid-filled spiral structure in the inner ear known as the cochlea. When sound causes these bones to move, they compress a membrane on one entrance of the cochlea and this causes the fluid inside to move accordingly.

Inside the cochlea are specialized "hair" cells that have symmetric arrays of stereocilia extending out from their surface. The movement of the fluid inside the cochlea causes the stereocilia to move. This physical change creates an electrical change and causes ion channels to open. The opening of these channels is monitored by sensory neurons surrounding the hair cells, and these neurons then communicate the electrical signals to neurons in the auditory association cortex of the brain.

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.

A few decades ago, a molecular complex called the tip link was discovered 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 years, the molecules that make up the tip link were not known. Now Mueller and his colleagues have identified one of the key proteins that forms the tip link - the protein cadherin 23.

The Molecular Detectives

The identification of cadherin 23 is a great example of molecular sleuthing.

For Mueller, who studies topics at the intersection of neuroscience and genetics, tip links appeared to be the key to 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 keep the stereocilia bundled. They also had evidence from studies of 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 the 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 show 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 predict that these 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.

The article, "Cadherin 23 is a component of the tip link in hair cell stereocilia" was authored by Jan Siemens, Concepcion Lillo, Rachel A. Dumont, Anna Reynolds, David S. Williams, Peter G. Gillespie, and Ulrich Mueller and appears as an Advance Online Publication (AOP) of the journal Nature on March 28, 2004. The article will also appear in print in an upcoming issue of the journal Nature. See

This work was supported by the National Institute on Deafness an Other Communication Disorders, The National Eye Institute, by a fellowship from the Boehringer Ingelheim Fonds, and by a C. J. Martin Fellowship from the National Health and Medical Research Council (Australia).

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