"It's a shame that youth is wasted on people too young to appreciateit."
That fragment of folk wisdom does not apply to a vanishingly smallnumber of young adults the world over whose youth is cut short bythe precocious onset of old age.
Abruptly, in their late teens or early twenties, these heirs to twostrangely mutated genes begin to show the stigmata and symptoms ofadvanced years _ graying hair, baldness, wrinkled skin, cataracts.Worse, they quickly acquire the deadly degenerative diseases _atheroscleroisis, cancers, cardiovascular failures, osteoporosis, TypeII diabetes _ expected in old age but amazing in the very young.They die in their fifties.
Curiously, Alzheimer's disease is not included in this roster of early-onset mortality.
It was just 90 years ago that a German medical student named OttoWerner described the first case of premature aging in a young person.Medical geneticists now know his discovery as Werner's Syndrome(WS). But they only know WS from the literature; it is so rare inmedical practice that even the scientists who know WS best are vagueas to its epidemiology.
"Its overall incidence in the U.S.," estimates molecular geneticistGerard Schellenberg, "is somewhere between 200 and 2,000 withWS. My best guess," he told BioWorld Today, "would be about 500,but it's going to be in that range. There are only three or four in theU.S. we even have contact with."
He added: "WS is a rare, recessive disease, so any time you haveinbreeding, for instance, first-cousin marriage, you're going to havehigher incidence of the disease. The carrier incidence, from whatlittle we know, is the same worldwide."
Schellenberg, an associate research director at Seattle's VeteransAffairs Puget Sound Health Care System, is senior author of a paperin today's Science titled: "Positional cloning of the Werner'ssyndrome gene."
A co-author, John Mulligan, is director of genomics at DarwinMolecular Corp., in Bothell, Wash.
"It was a completely entwined collaboration between the scientists atSchellenberg's lab and ours," said molecular biologist David Galas,chief scientific officer at Darwin.
To clone the WS gene, which sits on the short arm of humanchromosome 8, Galas told BioWorld Today, "We looked at the DNAof families in which WS was prevalent." That evidence exists in theform of deep-frozen cell lines from 70 or 75 WS families collectedover the years from all over the world by pathologist George Martinat the University of Washington, in Seattle.
The gene they mapped and cloned appears to encode an enzyme1,432 amino acids long, aptly named helicase, which unwinds thedouble helix of DNA. Thus, helicase sets up the strands for such vitaljobs as expression, replication or repair of the genetic material.
The researchers reported in Science that they had located fourmutations of the gene. "Since the paper was written," Darwin's Galassaid, "we've found several new mutations that cause WS. They arenonsense mutations or deletions."
He went on to explain that "the WS mutation knocks out thehelicase," but added the caveat: "We haven't proven yetbiochemically that it actually removes that helicase activity. Thoseexperiments are certainly in progress but the simplest hypothesis isthat it just takes out that helicase entirely."
WS Gene Causes Helicase Wipeout
Because WS is inherited recessively, a child born with two mutatedgenes, one from each carrier parent, "will have no helicase of thatparticular stripe," Galas pointed out.
"In yeast cells," he observed, "you can knock out that helicase, and itdoesn't lead to death. But the cell does have problems."
As for the problem with Werner's syndrome, he continued, "it is dueto a lack of helicase in every cell in the body."
"What we're actually doing already," Galas went on, "is trying tolook for other disease associations for different alleles [variants] ofthis gene, with diseases that we know are affected by WS, forexample, cardiovascular and cancers."
He cites patients with premature atherosclerosis _ a widespreadidiopathic affliction unrelated to either WS or aging _ in whom "wewould like to sequence their WS gene and see if there are specificalleles in it. We assume that there is some strong genetic component,and the question is: Does WS have anything to do with that? A quicklook at that is a really easy thing to do, now that we've got the gene."
What Darwin is looking for initially, Galas concluded, "is some sortof target for a small molecule that can be used to make a novel drug.All we really need is to identify the right disease, the right target andthen set up a cellular screen to find the right compound to do it."
Darwin and the Veterans Affairs administration filed a joint patent ontheir WS gene last year. (See BioWorld Today, Jan. 18, 1995, p. 1.)
Biochemist Anna McCormick is chief of the biology branch in theNational Institute of Aging, in Bethesda, Md.
The just-found WS gene and its helicase-knockout mutations, shetold BioWorld Today, "are the first evidence in humans that this cancause premature aging. WS, though not the perfect model, is a goodpartial model of human aging."
McCormick added, "What we hope to do now is try to make the linkand see if this [gene discovery] will tell us some things about normalaging. So we'll be funding the spin-offs in the future." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.