By David N. Leff
Imported cut-glass bowls, vases and goblets are traditional wedding presents and tourist trophies.
Picture a typical European glass-factory cutting area, the size of a high school gym, lined with pedestals holding the blown lead-crystal blanks. At each such work station stands an artisan, wielding a power-driven, diamond-tipped cutting tool, something like a dentist's drill.
This abrasive process fills the vast room with a high-pitched, whining screech. But in the background, loudspeakers broadcast soothing mood music — the kind you hear in office elevators.
How can the glass-cutters harken to this melodic Muzak over the shrill, deafening cacophony of the cutting tools?
A factory foreman explains: Over time, the workers tune out the high-frequency sounds, because the receptors in their ears attuned to these frequencies have been destroyed.
Those receptors are V-shaped rows of minuscule hair-like projections that line the inner ear's cochlea and convert acoustic vibrations into auditory nerve impulses in the brain's perception of hearing. The adult cochlea is equipped with some 30,000 of these ultrafine bristles, divided into rows of increasing length. Like organ pipes or piano strings, they resonate to the audible range of sound frequencies, from high to medium to low.
These thin, millimeter-long cilia, which interface between ear and brain, are themselves nerve cells, and as such die off with advancing age. This geriatric hearing loss has been called "premature senility of the inner ear." Only in birds and fish do the cochlear cilia regenerate.
Other traumas besides glass-cutting can destroy those cells and bring on hearing loss. A loud noise can do them in; so can maternal viral infection during pregnancy and certain antibiotics.
Many congenital syndromes, which damage primarily other organs, cause concurrent deafness. Such for example are Usher's syndrome, (retinitis pigmentosa and sensorineural hearing loss) and iodine deficiency in thyroid disease.
Then there's Waardenburg syndrome, marked by wide-set eyes and nostrils, a white forelock of hair and irises of different colors. And Jervell-and-Lange-Nielsen syndrome, in which individuals, already deaf, are at very high risk of sudden cardiac death from tachyarrhythmia.
But besides these syndrome-linked forms of hearing loss, there is also a kind of stealthy, complete deafness unrelated to any other etiology. It's called nonsyndromic deafness and is the cause of 70 percent of all hereditary loss of hearing. Up to 60 percent of the 28 million cases in the U.S. are thought to involve such inheritance.
The story of how one gene for nonsyndromic deafness was tracked down on the human genome, cloned and sequenced, begins 274 years ago, in the Costa Rican town of Cartago. There in 1713, a well-to-do Spanish landowner, identified only as "M," founded an afflicted family.
In his will, still extant, he mentioned that he had a hearing loss, and church records down through the years documented such deafness in succeeding pedigrees.
Fast Forward For Three Centuries
Eight generations later, his known living descendants now number 147, of whom 78 family members — almost exactly 50 percent — are deaf. That half-and-half ratio indicates an autosomal (i.e., not sex-linked), dominant mode of inheritance. It affects males and females equally.
In that extended Costa Rican kindred, children are born with normal hearing, but begin to lose low-frequency auditory perception between the ages of six and 20. By 30, they are profoundly deaf in all frequencies.
Molecular biologist Pedro Leon, at the University of Costa Rica in San Jose, saw in this statistically significant geneology the means of tracking down the gene or genes responsible for this nonsyndromic deafness. He and molecular geneticists Eric Lynch and Mary-Claire King, at the University of Washington, in Seattle, mapped that gene to human chromosome 5 five years ago.
Today's Science, dated Nov. 14, 1997, tells their story in an article titled: "Nonsyndromic deafness DFNA1 [associated with the human homolog of the Drosophila gene diaphanous."
Lynch, the report's first author, explained that DFNA1 stands for deafness, A for autosomal dominant, and 1 for the first such gene mapped.
He told BioWorld Today how, by linkage analysis of those 147 family members, the co-authors were able to map, clone, largely sequence, and test the mutant gene.
"In this paper," he recounted, "we identified all the DNA from an 800,000-base-pair region of interest on the long arm of chromosome 5 and sequenced it. Then, from the raw sequence, through database searching and computer predictions, we identified genes in the genomic region of interest.
"Next," Lynch continued, "we mutation-searched those genes and found one that has a specific mutation that's consistently co-inherited with the hearing loss in this Costa Rican family."
King, the paper's senior author, is known for having mapped the first gene for familial breast cancer, BRCA1, in 1991 while at the University of California, Berkeley. It was subsequently cloned three years ago. (See BioWorld Today, Sept. 19, 1994, p. 1.)
"We know more about DFNA1 one week after it was cloned," she observed in an interview, "than we know about BRCA1 three years after it was cloned. DFNA1," she continued, "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."
"A total of 3,511 base pairs (bp) of coding sequence have been identified," the paper reported; "about 250 bp remain to be determined."
That autosomal, dominant gene, DFNA1, when mutated, has now been declared guilty of causing progressive deafness in the descendants of its 18th-century founding ancestor, Señor. It's the human equivalent of a fruit-fly gene, called diaphanous, and is consistently mutated in the genomes of all 78 deaf M family members, but not in the 69 hearing ones, or 330 control individuals.
"The NFDA1 has a plausible biological story to it," Lynch observed. "It's involved in actin organization in the cell."
Mice First, Then (Maybe) Gene Therapy
Sound waves normally perturb and depolymerize those projections, which actin then repolymerizes. The co-authors suggest that the mutation blocks actin from doing this job, which is essential to hearing.
To test their hypothesis experimentally, Lynch said, "We'd like to try to recreate the phenotype in mice. We want to knock in the specific DFNA1 mutation into a mouse, and see if we can recreate this hearing loss by testing the effects of acoustic exposure on the animal. We'd want to progress toward understanding exactly what this mutation is doing in a model system, and if there's any way to undo it.
Asked how to undo it, Lynch observed: "The inner ear is a perfect target organ for attempting gene therapy, in that all its cells of interest are exposed." He concluded: "That's not really the goal of our lab. Other labs are working on gene therapy for hearing loss, and probably will be taking advantage of our findings." *