A postdoctoral fellow in the laboratory of University of Washington geneticist Dr. Mary-Claire King has succeeded in cloning a gene which, when mutated, causes an inherited form of deafness. The findings of Dr. Eric D. Lynch and colleagues are reported in the Nov. 14 issue of the journal Science.
The mutation in the autosomal dominant gene, DFNA1, is responsible for progressive hearing loss in a large extended family in Costa Rica. Of 196 family members identified in eight generations, 147 are still living and all participated in the research; 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.
“There are implications for general knowledge of hearing mechanisms,” said Lynch, who in 1992 mapped the gene to the long arm of chromosome 5, and completed cloning it just last month. “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 gives us some insight.”
The 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.
“While the mutation may be unique to this family, mutations in rare families hold the clues to universal biology,” said King, professor of medicine and genetics at the UW, 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.”
King praised Lynch, who has worked in her lab since 1991, for the quality of his work. “This is a pure example of the use of genomic sequencing to find genes. We mapped the gene, then captured 800,000 base pairs in clones. Eric personally did all of the sequencing. A single researcher can do this, because of the informatics and the equipment available here at the University of Washington.” King also singled out another post-doctoral fellow in her lab, biostatistician Dr. Ming K. Lee, who integrated a series of existing computer programs to facilitate the search for new gene sequences.
Dr. Pedro E. Leon of the Center for Research in Cellular and Molecular Biology at the University of Costa Rica identified the family whose inherited deafness led to the discovery of the gene. “This was a very successful international collaboration,” King said. “Pedro Leon’s analysis of the hearing and his characterization of the genealogy were perfect. Any gains to be made as a result of identifying this gene will be shared with the family.”
King also commented on the challenges of studying the genetics of deafness. “It’s very difficult because deaf people tend to marry other deaf people, and there may be more than one cause of deafness within a family.” In the case of the Costa Rican family, however, with the later onset of deafness they tended not to marry other deaf people, simplifying the search for the single gene. “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.
Additional co-authors are Jan E. Morrow and Dr. Piri L. Welsch of the King lab. The research was supported by the National Institutes of Health and the Markey Foundation.
In an accompanying News and Views article in Science, Elizabeth Pennisi describes a number of research efforts underway to find this and other genes involved in hearing loss.