Scientists Find Deafness Gene's Function
By Jason Socrates Bardi
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 has 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, 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
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
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 linkthe protein
The Molecular Detectives
The identification of cadherin 23 is a great example of
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 cellcell
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 familiesthe
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
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).
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