Hearing loss is the most common form of sensory impairment in humans; one in 1,000 children is born profoundly deaf and 10 percent of people over the age of 65 experience communication problems because of progressive hearing loss.
Although scientists have had a detailed understanding of the mechanics of the system for several decades (see sidebar) and knew that both genetic mutations and environmental trauma can cause deafness, it has been since only the mid 1990s that they have begun to learn how the ear works at the molecular level and what genetic mutations lead to deafness.
“Without information about the molecules it is impossible to develop real therapeutics,” says Christine Petit, a professor at the Pasteur Institute in Paris and a leader in the genetics of human deafness. To understand hearing impairment at the level of proteins, Petit and other researchers have worked to identify genetic mutations that cause deafness in humans. Already 42 genes have been identified, and another 40 or so are in the works.
Mutations in the human gene GJB2, which encodes the protein connexin26, are the most common cause of inherited deafness, and GJB2 was the first gene to be associated with hearing loss. Researchers have learned that the connexin26 protein works not in the sensory cells, but rather in the supporting cells nearby.
When the sensory hair cell detects a sound wave, the opening of its ion channels causes it to release neurotransmitters—glutamate and potassium—at the synaptic junction that connects it to the auditory nerve. Some of the neurotransmitter released is taken up by the auditory nerve itself, and is used to carry the signal to the brain. But scientists think it is the job of the supporting cells to quickly scavenge excess neurotransmitter molecules from the area so that the system is free to work when the next sound happens.
Petit and others suggest that mutations in connexin26 disable the supporting cells, prohibiting them from rapidly vacuuming up the glutamate and potassium and leaving the system insensitive to subsequent sounds.
Researchers have found that unlike GJB2, most of the genes that cause deafness do so in a small percentage of deaf people. Finding these genes is tricky. To Finding these genes is tricky. To do so, researchers often rely on large families in which several individuals are affected.
A three-dimensional model shows a portion of the POU4F3 gene. The yellow ribbon represents a portion of protein truncated because of a mutation in the gene, leading to hearing loss. Courtesy of Karen Avraham, Sackler School of Medicine, Tel Aviv University
Karen Avraham of Tel Aviv University and colleagues identified a mutation in the POU4F3 gene that is responsible for deafness in a large Jewish family. The scientists interviewed the family and took blood samples from family members interested in participating. They then drew a pedigree of the family and compared DNA isolated from family members who had significant hearing loss with that of hearing family members.
“The search for the gene … began when a member of the family, named Family H, contacted our laboratory at the Sackler School of Medicine,” Avraham says. The first ancestor the family knew to have suffered from hearing loss was a man born about 1843 in Libya. One of his four children inherited the progressive hearing loss. That individual had seven children, four of whom also suffered hearing problems, as did six out of seven children in the subsequent generation. “Most of our studies were done with this generation,” Avraham says.
The team narrowed down the location of the mutation that caused Family H’s hearing loss to a relatively small region of Chromosome 5, but they could not identify the specific gene from the family data, so they turned to mouse genetics for more detailed analyses. They identified the corresponding chromosomal region in the mouse genome, then tested the genes within that region to see if any encoded proteins that were expressed in the inner ear.
The researchers found that one of these genes, Pou4f3, was expressed in hair cells. Furthermore, mutations in the gene caused deafness in the mice.
With that information in hand, the researchers knew where to look in the DNA from affected Family H members. Sure enough, they found that these individuals, but not the hearing members of their family, were missing eight nucleotides in the POU4F3 gene. That mutation resulted in a nonfunctional protein.
The protein encoded by POU4F3 binds to DNA and regulates the activity of other genes. Avraham’s group has now started to identify some of these target genes, which themselves are critical for hair cell function. One of them is GFI1. When GFI1 is absent, the hair cells do not survive, which would lead to the type of progressive hearing loss seen in Family H.
Although researchers such as Avraham and Petit do not yet have ways to correct the mutations they have identified, this sort of information already has value to people who have deafness in their families, says
Richard J. Smith, director of the Molecular Otolaryngology Laboratory at the University of Iowa. Many of the families and patients he sees in his clinic want to have genetic testing done.
“If they have a child born deaf, they often have a lot of guilt wondering if they did something wrong—a concern that is not particular to deafness,” Smith says. “If it is a genetic mutation, at least you have an answer to what caused the problem.
Also, for some mutations, especially common ones such as GJB2, clinicians can use genetic information to help direct treatment and tell parents whether further deterioration in hearing is likely.
These human genetic studies may lead to molecular therapies. For example, scientists recently showed in mouse experiments that when they blocked the expression of another gene, Rb, support cells in the cochlea transformed into sensory hair cells. If investigators find ways to replicate the result in humans, they might be able to help people who have degenerative hearing loss because of damage to hair cells.
“That is the real challenge,” Petit says. “If we can move from hypothesis to treatment, and restore the function of the cochlea, that would be fantastic.”