Defect in protein can impede hearing,
Scripps research says
By Bruce Lieberman
UNION-TRIBUNE STAFF WRITER
April 19, 2004
The Scripps Research Institute
Tiny hairs arranged in bundles called stereocilia inside the
ear's cochlea convert sound waves into electrical signals
for the brain to interpret. San Diego scientists found that
the cadherin 23 gene creates tiny links, which tie the hairs
together and make hearing possible.
Scientists in La Jolla have identified the critical role a
single gene plays in the ability to hear: the point at which
sound waves in the inner ear are transformed into electrical
signals to the brain.
The gene, cadherin 23, had already been pinpointed as one
of about 100 genes involved in hearing. But exactly where
in the inner ear it played a role, and how, was unknown.
Mutations in the gene have been implicated in deafness, including
the devastating disease Usher syndrome, which causes both
deafness and blindness.
"We know a lot about our sense of vision and smell and taste,
but we have (had) no clue about the molecules which help us
convert mechanical energy into electrical signals," said Ulrich
Mueller, a scientist at The Scripps Research Institute in
La Jolla whose study will appear in the journal Nature in
coming weeks. The paper was released online this month.
Cadherin 23 "is now the first molecule," Mueller said in an
While this latest finding is important, scientists cautioned
that it is only one step toward understanding the complex
genetic architecture that supports hearing. Whether it will
someday lead to new treatments for deafness and diseases is
uncertain. The gene, the researchers found, encodes a protein
in the cochlea, the snail-like organ of the inner ear that
marks the last passage of sound waves from the outside world
before they are converted into electrical signals that the
brain can then interpret.
Inside the cochlea are bundles of tiny hairs that are pushed
against a membrane as sound waves traveling through a fluid-filled
chamber underneath them exert pressure.
The hairs, called stereocilium, are arranged in bundles called
stereocilia. The tip of each hair is bound to the one next
to it by a tiny link, somewhat like a string tying two branches
of a tree together.
The cadherin 23 gene, the researchers found, encodes a protein
that makes these strings. Without them, hearing is impossible.
As the entire bundle of hairs bends to the pressure of sound
waves, the strings pull at the hairs they are attached to
opening a kind of door on the surface of each hair.
The door, called an ion channel, allows calcium and potassium
ions floating in fluid inside the cochlea to flow into each
hair and down toward vesicles leading to the brain.
The flow of ions from the cochlea and into the brain marks
this transformation of sound waves into electrical signals
a process called mechanotransduction.
"Something has to open this door, and this molecule that we're
working on, cadherin 23 is a component of this machinery which
helps open it," Mueller said.
His research team identified the role of cadherin 23 by scanning
all known proteins in the human and mouse genomes to see which
one fit the profile of proteins of the type that had already
been associated with stereocilia.
They zeroed in on two families of genes: cadherins and integrins.
They narrowed the field down to cadherin 23 based on its size
and its known association with deafness and Usher syndrome.
Their next step was to see if laboratory animals genetically
engineered without the cadherin 23 gene would also not have
the links. Experiments with zebra fish, with researchers at
the Oregon Hearing Research Center and Vollum Institute at
Oregon Health & Science University, showed that very result.
While the cadherin 23 protein works to open the ion channels,
another one called myosin 1c appears to play a role in closing
them. Mueller said he hopes to build an even more complete
"This (finding) gives us the opportunity to find other molecules
that are associated with this, which plays into this very
fundamental process," he said.
Konrad Noben-Trauth, a researcher at the National Institute
on Deafness and Other Communication Disorders, at the National
Institutes of Health, first identified the cadherin 23 gene
in 2001, and suspected that it was important for stereocilia.
Exactly how it worked was unknown.
The Scripps study "is one step forward in understanding the
structure of the bundle and of mechanotransduction, the first
step in the hearing process," Noben-Trauth said.
"There are still some questions open on this study, and I
would argue that this finding needs further proof."
More work will be needed to show that the cadherin 23 gene
actually holds the instructions for the links, he said. A
separate experiment with mice, meanwhile, will be needed to
show that mammals without the gene also never grow the links.
Mueller called the work an example of how the study of a
deafness can help scientists better understand basic physiology.
"Disease has really helped us to define a component of a very
fundamental biological process, and that helps us to gain
an understanding of the disease," he said.
Bruce Lieberman: (619) 293-2836; firstname.lastname@example.org