By David N. Leff

Shakespeare diagnosed the syndrome of "second childishness" — old age — in his immortal line, "Sans teeth, sans eyes, sans taste, sans everything."

That "everything" certainly embraced sans hearing — the progressive loss of sound perception with advancing years of life. Hence, the expanding baby-boomer market for hearing aids.

But members of a large five-generation family in Israel begin to go deaf in the prime of life. Scoping their genome has revealed a gene sequence deletion that explains their inherited early-onset loss of hearing.

Today's Science, dated March 20, 1998, tells the story in a research report titled "Mutation in transcription factor POU4F3 associated with inherited progressive hearing loss in humans."

The paper's senior author is molecular geneticist Karen Avraham, at Tel Aviv University, in Israel. Her 14 co-authors include research teams at the National Institute on Deafness and Other Communication Disorders, in Bethesda, Md., as well as investigators at the University of Washington, in Seattle, and Harvard Medical School.

The article identifies that informative kindred as "Family H." It traces their pedigree back to a genetic founder of its familial deafness, born in Libya in 1843. His 80 living descendants are now settled in Israel, with outlying branches in Belgium and the U.S.

"We didn't need everyone in the H kindred in order to go after the gene," Avraham told BioWorld Today. "We were able to get the information we needed from 23 of them, including all of their Belgian and American family members, but omitting everyone under 40 years of age."

Of 36 individuals in that family tree going back five generations to 1843, 19 developed deafness in mid-life; seventeen did not.

Family In Study Not Considered Unique

"What's unique about Family H," Avraham observed, "is that there's nothing unique about Family H. They're just an average family, from all walks of life — urban, rural, very diverse in terms of occupation and places of residence. The fact that they are regular families," she pointed out, "is important, because their progressive deafness is something that affects so many people in the world."

"Progressive hearing loss impairs a staggeringly large proportion of our population," said research otologist Karen Steel. "Sixteen percent of adults, and more than one-third of those over 60 years old, have a hearing loss of 25 decibels or more, so they might benefit by wearing a hearing aid."

Steel wrote an editorial accompanying Avraham's report in Science, titled: "Progress in progressive hearing loss." She is at the British Medical Research Council's Institute of Hearing Research, in Nottingham, U.K.

Those cochlear hair cells, which transmit their sonic messages to the brain via neuronal pathways, do not regenerate. Hence they require perpetual molecular maintenance, provided by transcription factors bearing the generic name of POU.

"A lot of these transcription factor genes have been isolated in recent years," Avraham noted, "and they all share a common genomic region, now known as the POU region. Their role, she explained, "is to bind to and regulate other genes. Tell them when to turn on, and when to turn off, in different cells.

"POU4F3," she added, "is a gene responsible, we believe, for the fetal development and maintenance through life of the sensory hair cells of hearing. We know that from work done in knockout mice, in which this transcription factor was obliterated completely. The mice were born profoundly deaf. And they had no inner-ear hair cells."

Molecular geneticist Mary-Claire King, of the University of Washington, in Seattle, is a co-author of the Science paper. "Humans hear very much the same way mice do," she observed, "so what Karen [Avraham] and her colleagues have learned about deafness in mice is immediately transferable to finding genes for inherited deafness in human families." King added, "Genome technology provides a perfect trap to catch these genes."

Avraham and her lab team in Tel Aviv set that trap by collecting blood from their Family H members, both deaf and hearing.

Only Six Of 100 Hearing Genes Isolated So Far

"We made the DNA," she recounted, "and screened for markers by linkage analysis, trying to identify the chromosomal location of the defective gene in this kindred. About 31 deafness loci have already been mapped on the human genome. It's estimated," she observed, "that there are going to be as many as 100 genes involved in normal hearing and causing deafness. But only about six have been isolated so far."

When no human gene turned up, the group turned to those Pou4F3-minus knockout mice. "That murine sequence on mouse chromosome 18," Avraham went on, "looked like a perfect candidate for causing deafness in a human family. So the next thing we did was isolate the corresponding human gene, on the long arm of chrosomsome 5. Then we sequenced the DNA from both affected and unaffected Family H members. We found that the hearing-impaired among them had an eight-base-pair deletion in this gene."

The gene itself is a scant kilobase long, "which makes it very amenable to screening," Avraham pointed out. "And of course the next step which we're now interested in doing — and which I'm sure a lot of people will do once this news comes out — is to start screening the rest of the hearing-impaired population for mutations in this gene.

"Alternatively," she continued, "if we never find mutations anywhere else than in this H family, it's still an important finding. It will tell us a lot about the function of the inner ear and how deafness is caused."

At present, she sees no therapeutic intervention on the horizon of this discovery. But over that horizon, "several groups in the world are working on hair-cell regeneration and gene therapy."

Meanwhile, in the here and now, Avraham concluded, "it becomes possible to advise individuals harboring the gene deletion that they are going to lose their hearing. And counseling them to avoid phonal or acoustic traumas — incredibly loud noises — which will make their hearing worse." *

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