Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scripps Research scientists find deafness gene’s function

29.03.2004


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 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 http://dx.doi.org/10.1038/nature02483.


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).

Jason Bardi | EurekAlert!
Further information:
http://www.scripps.edu/
http://dx.doi.org/10.1038/nature02483

More articles from Life Sciences:

nachricht Molecular evolution: How the building blocks of life may form in space
26.04.2018 | American Institute of Physics

nachricht Multifunctional bacterial microswimmer able to deliver cargo and destroy itself
26.04.2018 | Max-Planck-Institut für Intelligente Systeme

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Why we need erasable MRI scans

New technology could allow an MRI contrast agent to 'blink off,' helping doctors diagnose disease

Magnetic resonance imaging, or MRI, is a widely used medical tool for taking pictures of the insides of our body. One way to make MRI scans easier to read is...

Im Focus: BAM@Hannover Messe: innovative 3D printing method for space flight

At the Hannover Messe 2018, the Bundesanstalt für Materialforschung und-prüfung (BAM) will show how, in the future, astronauts could produce their own tools or spare parts in zero gravity using 3D printing. This will reduce, weight and transport costs for space missions. Visitors can experience the innovative additive manufacturing process live at the fair.

Powder-based additive manufacturing in zero gravity is the name of the project in which a component is produced by applying metallic powder layers and then...

Im Focus: Molecules Brilliantly Illuminated

Physicists at the Laboratory for Attosecond Physics, which is jointly run by Ludwig-Maximilians-Universität and the Max Planck Institute of Quantum Optics, have developed a high-power laser system that generates ultrashort pulses of light covering a large share of the mid-infrared spectrum. The researchers envisage a wide range of applications for the technology – in the early diagnosis of cancer, for instance.

Molecules are the building blocks of life. Like all other organisms, we are made of them. They control our biorhythm, and they can also reflect our state of...

Im Focus: Spider silk key to new bone-fixing composite

University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.

Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.

Im Focus: Writing and deleting magnets with lasers

Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.

Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

IWOLIA: A conference bringing together German Industrie 4.0 and French Industrie du Futur

09.04.2018 | Event News

 
Latest News

World's smallest optical implantable biodevice

26.04.2018 | Power and Electrical Engineering

Molecular evolution: How the building blocks of life may form in space

26.04.2018 | Life Sciences

First Li-Fi-product with technology from Fraunhofer HHI launched in Japan

26.04.2018 | Power and Electrical Engineering

VideoLinks
Science & Research
Overview of more VideoLinks >>>