Steps Towards Treating Genetic Deafness
By Jason Socrates Bardi
"Jack" and "Dianne" are hard working midwesterners, sweethearts
since high school, loving parents, and both carriers of a
recessive gene defect that they are not aware of. Jack and
Diane have four children and their youngest, call him "Jake,"
has the misfortune to have inherited copies of the bad gene
from both parents.
Despite the fact that his parents and older siblings are
all generally healthy, Jake is born without the ability to
hear. Hearing aids prove to be of no help, so Jake, his parents,
and siblings all learn sign language.
Jake has other problems, too. He has trouble balancing and
is a late walkernot taking his first steps until he
is almost two years old. Throughout his childhood, he has
to hold on to something solid when he sits down. Around age
10, the real trouble starts. Jake starts to have difficulty
seeing at night, and by the time Jake is in his late teens,
he is completely blind and no longer able to communicate.
Welcome to the world of Usher syndrome.
Even if the imaginary couple described above knew their
son had the very real and devastating genetic disease Usher
syndrome, there would not be much they could do. For there
is no cure for Usher syndrome, the leading cause of deafblindness
in the United States.
In his laboratory space overlooking the East Torrey Pines
Mesa, Associate Professor Ulrich Mueller reflects on this
problem and how it relates to his decision to bring his laboratory
and research program here from the Friedrich Miescher Institute
in Basel, Switzerland. He is one of the newest members of
the Department of Cell Biology at The Scripps Research Institute
(TSRI) and a member of TSRI's Institute for Childhood and
Neglected Diseases (ICND).
The ICND was a good fit for him scientifically, he says,
because it has a number of researchers who study questions
related to nervous system development and function. This complements
his own interest in Usher syndrome and topics at the intersection
of neuroscience and genetics.
Mueller is also concerned with other human genetic diseases
related to mechanosensory preception, and there are a vast
number. "One in 800 children is born hearing impaired," he
says, "And age-related hearing loss is also a big problem
in society." In fact, nearly two thirds of all people over
the age of 70 suffer from serious hearing loss.
Out in the laboratory, signs of his recent move are everywhere.
Half-unpacked boxes; large equipment looking for a permanent
home; a pan with paint and a roller brush in it. Still, the
laboratory looks amazingly busya few students or postdocs
can be seen filling shelves. Mueller and his laboratory can
count the number of weeks they have been here on one hand,
and they can't wait to get started.
"Next week, we start doing experiments," says Mueller.
Leading Cause of DeafBlindness
The experiments that Mueller and his laboratory will begin
next week concern a number of questions related to Usher syndrome
and the underlying biology of mechanosensory perception, a
broad area encompassing not only hearing, but also balance,
and a number of other bodily functions, such as blood pressure
and gastrointestinal regulation. Hearing, balance, and these
other activities are all regulated by receptors that sense
our physical environmentsound waves or positional cues,
for instanceand change physical signals into electrochemical
Usher syndrome was first described by the pioneering German
eye doctor Albrecht Von Graefe in 1858 and is named after
a contemporary of Von Graefe, the British doctor Charles Usher,
who believed that this condition was inherited, passing from
parents to their children.
About 10 percent of children who are born deaf have a form
of Usher syndrome, and it is the major cause of deafblindness.
According to the National Institute on Deafness and Other
Communication Disorders, which is one of the National Institutes
of Health, more than half of the estimated 16,000 deaf-blind
people in the United States are believed to have Usher syndrome.
Treatments for Usher syndrome tend towards the adaptivehearing
aids, cochlear implants, orientation and mobility training,
auditory training, and Braille instruction. Perhaps the dearth
of preventative therapies or cures is not surprising given
that the syndrome is not well understood.
"We focus on [Usher syndrome] both to learn something about
the disease but also about mechanosensory preception," says
Mueller. "The process of mechanosensory preception is not
at all understood."
Finding the Genes that Cause Deafness
What is understood is the basic anatomy of mechanosensory
perception, hearing, and deafness.
It all starts in the inner ear. Therein resides an organ
called the cochlea, which detects physical sound waves. Also
in the inner ear is the vestibule, which is an organ that
detects gravity and motion. The close proximity and the identical
components of these two explains something about the tendency
for hearing and balancing problems to be closely related.
When waves of soundfrom a shattering window, for instancehit
a person's ear, they travel into the ear cavity and hit a
group of "hair" cells that lie within the cochlea. These are
the sensory cells that actually detect the sound with arrays
of actin-rich, hair-like "stereocilia" projecting from their
surface. These stereocilia are connected to each other and
move as a bundle, and when they move, ion channels in them
open, letting ions pass into the cells, change the polarization
of the cells, and alter the release of neurotransmitters from
the hair cells.
This change is monitored by sensory neurons and other support
cells surrounding the hair cells, which then communicate electrical
signals of their own to the brain, where neurons in the auditory
association cortex can then fire and interpret the sound as
In Usher syndrome and other "sensory neuronal" diseases
that cause deafness, the hair cells in the cochlea are unable
to maintain the symmetric arrays of what are known as "stereocilia."
Somehow the genetic defects cause the stereocilia to splay
and degenerate instead of making bundles.
"These are not structural abnormalities of the bones," says
Mueller, "but a disease that directly affects the morphology
of the sensors."
But this basic picture falls far short of being useful for
designing therapies because it lacks the identities and mechanisms
of action of many of the receptors and other molecules that
control these processesthe ion channels, for instance,
have never been identified. Mueller estimates that there are
more than 150 separate genetic loci involved in diseases that
cause deafness, and only a fraction of the genes in these
loci have actually been cloned.
Finding ways to treat disorders in mechanosensory perception
without these details is like trying to describe a pantomime
you watched in the dark.
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