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 walker—not 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 deaf–blindness 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 busy—a 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 Deaf–Blindness

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 environment—sound waves or positional cues, for instance—and change physical signals into electrochemical ones.

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 deaf–blindness. 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 adaptive—hearing 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 sound—from a shattering window, for instance—hit 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 breaking glass.

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 processes—the 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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Associate Professor Ulrich Mueller recently moved his laboratory and research program to TSRI. Photo by Jason Bardi.