Secrets of Deafness

One in every 10 Americans is deaf or has a serious hearing loss. Although loud rock music, antibiotics and accidents account for many of those 28 million cases, at least 60% are genetic in origin.

Researchers already know of more than 50 genes that can cause deafness when they are defective, but each of those accounts for only a relatively small percentage of cases. The major genetic causes of hearing loss have remained elusive--at least until recently.

Over the last year, four new deafness genes have been identified, and it now seems likely that at least one of them is responsible for a large proportion of inherited hearing loss.

At the very least, these discoveries are shedding light on how the ear works. But perhaps more important, they are also offering the promise of screening infants for deafness at birth. That would allow deaf infants to be taught sign language at a very early age, thereby keeping them from falling behind in their language acquisition skills.

Such genetic screening “is the single most important test [for deafness] that has yet come to hand,” said geneticist William Reardon of the Institute of Child Health in London.

Scientists recognize two major forms of inherited deafness, called syndromic and non-syndromic. In syndromic deafness, defects in a single gene cause a variety of medical problems, one of which is deafness. In Usher syndrome, victims are deaf and blind. Waardenburg’s syndrome is marked by deafness, a white forelock of hair and widely spaced eyes that are often of different colors.

Researchers have identified more than two dozen genes that cause syndromic deafness.

But at least 70% of hereditary deafness is non-syndromic: In these cases, deafness is the only symptom of a genetic defect. Before last year, only three genes for non-syndromic deafness were known.

Two of those are in intracellular energy factories called mitochondria. The third is on the sex-determining X chromosome, one of the 23 pairs of chromosomes that make up the genetic blueprint of a human. All three of these mutations are rare, however.

The search for other deafness genes has been frustrating because of a phenomenon that geneticists delicately refer to as assortative mating. Simply put, deaf people tend to marry other deaf people. Then, because the husband and wife in most cases owe their hearing loss to different genes, assortative mating makes it very difficult to track a gene through several generations of a family, the technique commonly used to discover disease-causing genes.

Researchers must thus turn to isolated families where it is likely that a single gene has been passed down for long periods of time. One such family is the “M” family of Costa Rica, which traces its ancestry to Spanish traders who settled in the Americas in the 1600s.

One branch of the family, founded in 1713 by a wealthy Spanish landowner in the town of Cartago, has been marked by deafness for eight generations. Today, nearly half of the 147 family members suffer from hearing loss that begins at about age 10 and leads to total deafness by age 30.

In November, a team headed by geneticists Eric Lynch and Mary-Claire King of the University of Washington reported the discovery on chromosome 5 of a gene called DFNA1 that causes the family’s hearing loss.

Large families in China and Tunisia were studied in the discovery of a second deafness gene, called myosin VIIA. One mutation in that gene causes Usher syndrome. But British geneticists Karen Steel and Steve Brown of the Medical Research Council laboratories in Nottingham and Harwell, respectively, found last year that other mutations cause only deafness.

This gene is very unusual in that the nature of the mutation can change its transmission pattern. One class of mutations is recessive, so that a child must receive a copy of the defective gene from each parent for deafness to occur. Other mutations are dominant, so that only one defective gene is sufficient to cause the hearing loss.

The team also reported in November that the myosin VIIA protein plays a key role in the accumulation of certain antibiotics inside the hair cells of the ear, leading to deafness.

“Myosin VIIA is clearly involved in a spectrum of deafness,” Steel says.

The discovery of another gene that causes both syndromic and non-syndromic deafness was reported in December by a team from the National Human Genome Research Institute, who were studying Pendred syndrome.

Geneticist Eric D. Green and his colleagues found that Pendred is caused by mutation of a gene on chromosome 7. They also found, however, that other mutations of the gene cause only hearing loss. They estimate that defects in this gene cause as much as 10% of all cases of hereditary deafness.

But perhaps the most common gene discovered to date is called connexin 26. A team from the University of London and St. James’ University Hospital in Leeds found it while they were pursuing what they believed to be a syndromic gene causing deafness and skin problems.

They reported in May that the deafness was caused by connexin 26, while the skin problems are caused by another, as-yet unidentified gene. In November, geneticist Christine Petit of the Pasteur Institute reported that defects in connexin 26 were present in 39 of 65 large families that she and her colleagues studied.

Earlier this month, Dr. Xavier Estivill of the Hospital Duran i Reynals in Barcelona reported finding connexin 26 defects in half of 82 families that he studied, as well as in 37% of patients with sporadic deafness. He and his colleagues estimated that one in every 31 people carries the defective gene, a higher frequency than the carrier rate for cystic fibrosis.

“It’s clearly a major contributor to deafness,” said molecular geneticist Thomas Friedman of the National Institute on Deafness and other Communication Disorders.

Researchers do not yet know precisely how each of these defects produces deafness. Myosin VIIA and DFNA1 apparently are important in maintaining the structure of stereocilia, projections on the hair cells of the ear that bend when sound waves vibrate the fluid in which the cells are bathed. The movement of the stereocilia causes the cells to fire electrical signals toward the auditory nerve.

The Pendred protein seems to be responsible for transporting sulfate ions into cells. Defects in other sulfate-transporting proteins are known to cause a form of congenital diarrhea and a severe form of dwarfism.

The connexin 26 protein helps form so-called gap junctions--electrical channels connecting cells. A defect in it may interfere with transmission of electrical signals to the auditory nerve.

Experts predict that as many as a half-dozen other deafness genes may be isolated in the coming year. “We’re on the brink of a whole new understanding of the molecular dynamics of hearing,” Lynch said.

The Hereditary Hearing Loss home page provides the latest information on the search for genes that cause deafness: https://dnalab-www.uia.ac.be/dnalab/hhh

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The Hearing Genes

The ear is a complicated mechanism whose function can be disrupted at a variety of sites.

Researchers have recently found four genes that produce such interference, causing deafness without other symptoms. The sites where three of the genes are thought to act are shown by the colors. The fourth works throughout the ear.

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Cochlea

Inner hair cell

Stereocilia

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Suspected sites of action

DFNA1

Myosin Vlla

Connexin 26

Source: Science