By David N. Leff

Blindness and deafness count their victims in the millions worldwide. People born both blind and deaf are mercifully fewer, but their number is still horrendous.

This combined loss of vision and hearing goes by the name of Usher's syndrome, after a British ophthalmologist, Charles Usher, who described it in 1935.

The affliction strikes about four of every 100,000 live births in the U.S. — more than half of the 16,000 victims who inherit blindess and deafness together. Many also have balance problems.

Usher's syndrome (USH) comes in three levels of severity. Here is how Boystown National Research Hospital, in Omaha, Neb. — a leading center of USH research — describes the three types:

* Type I — born with a profound hearing loss, and considered deaf from birth; retinitis pigmentosa ensues.

* Type II — born with a moderate to severe hearing loss, and considered hard of hearing; retinitis pigmentosa.

* Type III — hearing loss that gets worse as the person ages; retinitis pigmentosa.

"Type II Usher's syndrome," said molecular geneticist Janos Somegi, at the University of Nebraska, in Omaha, "accounts for over half of all USH cases — 59 percent of our 560 Type II families." He added that "their blindness usually occurs in adolescence, after 16, 17 or 18 years of age."

Somegi pointed out that USH "is inherited as an autosomal recessive disease. This requires that the mother and father should each have one bad copy of the USH gene and should give those mutated copies to their offspring, who then develop the syndrome."

Somegi is senior author of an article in a recent issue of Science, dated June 12, 1998, in which he reports identifying the hitherto-unknown USH-II gene. Its title is "Mutation of a gene encoding a protein with extracellular matrix motifs in Usher syndrome Type IIa."

Gene For Type I USH Already Known

Molecular geneticist William Kimberling, of Boystown, a co-author of that paper, discovered the gene for the more severe Type I USH three years ago, in 1995.

"As our collaborator in the Science paper," Somegi told BioWorld Today, "Kimberling did the initial genetic analysis, which directed us to the chromosomal region on the human genome where we had to look for the gene."

That linkage-analysis mutation hunt involved 96 USH-II patients from 11 laboratories in five countries. It pinpointed the rogue gene to the long arm of human chromosome I, and turned up three separate mutations that occur exclusively in USH-II individuals.

That candidate gene, Somegi pointed out, is expressed in the adult retina and fetal eye, as well as in the inner-ear cochlea of newborns. Retinitis pigmentosa is among the commonest causes of blindness. (See BioWorld Today, March 25, 1998, p. 1.)

Of the 96-patient cohort, 21 tested positive for the most frequent of the three mutations. Eight of them had inherited the bad gene from one parent (heterozygous), 13 from both (homozygous).

"All but two of these individuals," the Science paper noted, "had northern European ancestry (Swedish, Dutch, German or English)."

Somegi sees his Type II gene discovery as promising one early payoff — a diagnostic tool for this commonest form of Usher's syndrome.

"What I, and everybody working in this area feel," he observed, "is that this certainly improves the outlook for diagnosis. Because we can now screen for mutations in the gene.

"It can be used for prenatal diagnosis," he went on, "if somebody or a laboratory wishes to introduce it. Not by cytogenetics, but by genetic testing. It would be as accurate as any genetic testing could be.

"According to an estimate," Somegi pointed out, "there are approximately 23,000 USH-II patients in the U.S. I think that prenatal diagnosis could be important, if affected individuals married and are expecting children. Already now there are some techniques that can delay the development of retinitis pigmentosa. But of course the infants are born with hearing impairment, which cannot be delayed." (See BioWorld Today, May 29, 1998, p. 1.)

As to how soon such a service might become available, Somegi posed a demurrer: "I think here one has to make an assessment about financial factors: how much it would cost, and how many patients can be involved. As far as I know," he added, "our collaborator, Kimberling at Boystown, may introduce genetic testing on Usher-II genes in the future. Boystown National Research Hospital is specialized for hearing and speech disorders, so they are collecting patients there."

Diagnosis is one thing, therapeutic potential quite another.

"Concerning therapy," Somegi stated, "I'm not so determined to give a positive answer. By discovering genes like the Usher-II gene, what I feel could be important is that we learn more about the biochemical and physiological processes of hearing, as well as of vision, so we can conclude what might have gone wrong at the molecular level. That may help in the future to design therapies."

To which he appended the observation that "I would never suggest that, with this USH-II gene, gene therapy is something that is very close."

Nebraska/Boystown Team Tackles New Agenda

Meanwhile, he and Kimberling are continuing their six-year joint genetic assault on Usher's syndrome, "trying to identify three other gene sequences, for USH-Type III and variants of Types I and II.

"On the Type II sequence described in our Science paper," Somegi said, "we will concentrate on the protein product to find out which cells express the normal protein in the retina and the inner ear. What is its subcellular localization? Where is the protein inside the cell? And what could be its function? Does it interact with other proteins? Does it receive information coming from another cell? Or from outside the cells?"

On this point, Kimberling allowed, "If the protein linked to the gene is found outside cells, it may be possible to just work with the protein to try to develop therapies. If the protein is inside cells — the case with the Type I gene — this approach is not possible."

To pursue their agenda, the two laboratories plan to recruit and condition mice.

"We are looking for a model system," Somegi said, "where we can study this disease, looking for a mouse homolog of this gene. In order to do reverse genetics. We need to make knockout and transgenic mice," he concluded, "either to delete this gene from murine strains or overexpress the gene in other strains." *

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