A Gene for Hearing, and Hearing Loss

Caption: Family Tree Showing Three Generations of Hearing Loss (click for larger version)
 
The discovery and cloning of the gene is a culmination of more than 20 years of research. The story began when a scientist in Costa Rica, Pedro León, at the University of Costa Rica, began to investigate the case of a family in which a high percentage developed deafness. The "M family" traces its ancestry to Spanish explorers who settled in the Americas about 1600. The family can also trace a long history of deafness among its members.

Of 196 family members identified in eight generations, 147 are still living and all participated in the research. Some 78 family members are deaf. Onset of deafness commences between age 6 and 20, and is complete by age 30. The gene mutation that causes their total hearing loss has been traced to a common ancestor, a man born in Costa Rica in 1713. The mutation causes no abnormalities other than deafness, and is found equally in males and females.

University of Washington geneticists mapped the gene associated with the hearing loss  to the long arm of chromosome 5 in 1992. A mutation in the autosomal dominant gene, DFNA1, is believed to be responsible. The gene has now been isolated and cloned.

The DFNA1 gene encodes a protein called human diaphanous 1, which interacts with a major structural protein called actin. Actin helps to stiffen an array of filament-like projections at the ends of the stereocilia, the hair cells of the  inner ear that turn sound waves into electrical impulses that stimulate the auditory nerves. The projections are perturbed or depolymerized by sound waves, and normally are repolymerized by actin in order to function again. The researchers believe the gene may not allow the actin to repolymerize, preventing the hair cells from responding to sound waves.

"There are implications for general knowledge of hearing mechanisms," said Eric Lynch, geneticist at the University of  Washington.  "We understood that the actin cytoskeleton is critical to normal hearing, but we didn't know how it was being formed and maintained. This gene give us some insight."

"While the mutation may be unique to this family, mutations in rare families hold the clues to universal biology," noted Dr. Mary-Claire King, professor of medicine and genetics at the University of Washington, who mapped the first gene for inherited breast cancer  (BRCA1) in 1991. "We know more about DFNA1 one week after it was cloned than we know about BRCA1 three years after it was cloned. DFNA1 is a mutation of an ancient gene descended from a gene in yeast, fruit flies and mice; it is critical to basic functions of cell division," she added.

The research is an excellent example of  the use of genomic sequencing to find genes. By analyzing DNA from 147 family members, 78 of whom had lost their hearing, the researchers were able to narrow the location of the faulty gene to an 800,000-base pair region on chromosome 5. They sequenced that portion of the chromosome and checked the resulting sequence against genes or partial genes on file in the public database called GenBank. The computer searches turned up more than 15 candidate genes, one of which was DFNA1, a gene previously identified in fruit flies and mice. This gene is consistently mutated in the deaf members of the Costa Rican family, but not in unaffected members or in unrelated controls.

The DFNA1 gene is the third gene associated with inherited forms of deafness isolated in the last year. All three of these genes are associated with non-syndromic forms of deafness, that is, hearing loss is the only problem associated with the gene defect. This is considered particularly important because 70% of hereditary deafness is nonsyndromic, and up to 60% of the 28 million cases of hearing loss in the United States are thought to have a hereditary component.  Researchers have also cloned more than two dozen genes that cause "syndromic" deafness. In these cases, the deafness is accompanied by other symptoms, such as blindness or pigment abnormalities.

"Now that this gene is cloned, many groups will be able to test for variations in it," said King. "The research is blossoming at an extraordinary pace." Further research will involve introducing the mutated gene into a mouse model.

The research appears in the Nov. 14, 1997  issue of the journal Science.