Special To BioWorld Today
BETHESDA, Md. _ In the biggest new-gene media event since lastSeptember's announcement of the first familial breast-cancer gene,the National Institutes of Health on Thursday introduced the DNAsequence for a rarer hereditary disease _ ataxia-telangiectasia (AT),with even more important potential implications.
Today's issue of Science reports discovery of the AT gene by aconsortium of 30 researchers from 13 centers in seven countries onfour continents. They studied 176 AT families from five countries.
Co-author Francis Collins, who directs the National Center forHuman Genome Research here, joined the project's senior author,Israeli geneticist Yosef Shiloh, at the news briefing. Shiloh, aprofessor at Tel Aviv University, led the transnational investigationthat tracked AT's single gene to its locus on human chromosome 11.
The researchers found that AT's pattern of inheritance is autosomalrecessive, which means that the lethal childhood disease strikes downone in four offspring _ homozygotes _ who receive a mutant formof the gene from both father and mother. But each such heterozygousparent, carrier of one AT gene mutation, is, at least conceptually, fourtimes as likely to get cancer than the population at large, and has fivetimes the risk for hereditary breast cancer.
An estimated 1 percent of the population _ 2.5 million people in theU.S. alone _ are carriers of AT gene mutations.
In Greek, the words "ataxia" and "telangiectasia" mean, literally,"disorder" and "expanded blood vessels." Clinically, ataxia signifies"loss of balance." To its victims, AT means a short, anguished lifeand early death.
Human geneticist Michael Swift, who directs the Institute for GeneticAnalysis of Common Diseases at New York Medical College inValhalla, N.Y., has studied AT for a quarter century. "Kids showsymptoms in the first year of life, when they begin to walk" he toldBioWorld Today. "All too often, the pediatrician dismisses parentalconcern over a toddler who wobbles by saying, `You're just ananxious mother.' "
In fact, progressive loss of balance and of muscular coordinationarises from the wasting of Purkinje nerve cells in the brain'scerebellum.
The second salient sign of AT, dilated blood vessels, doesn't show upuntil age five or six, Swift continued. These visibly swollen red veinsand arteries are most apparent on the eyeballs, nose and facial skin.
Meanwhile, grimmer effects of the disease are destroying the immunesystem, attacking lungs with antibiotic-proof, and eventually fatal,infection, and the blood with deadly lymphomas and leukemias. ATchildren used to die in the first decade of life, Swift said, "but withbetter medical management, they probably survive today, on average,beyond age 20," though usually in wheelchairs.
An estimated 500 children in the U.S. are known to have AT, whereSwift estimates its incidence at perhaps one in 90,000 live births. InIsrael, Shiloh has found a far higher prevalence among Jewishimmigrants from Morocco. Italy and Turkey, he said, are AT's othermain foci.
Gene Encodes For Human's Largerst Protein
"The AT gene encodes for a huge protein," Shiloh said at a pressconference here, "one of the largest in the human body. That proteinappears to play a role in the life cycle of cells, and in the response ofcells to DNA damage.
"[Our discovery,] he added, "is just the end of the beginning. Thenext step is to develop treatments. Immediate practical results couldinclude the ability to identify AT patients, do prenatal diagnosis inAT families, and ultimately carrier-detection."
Seconding this outlook, Collins added, "One area of deep concern isthat insurers might use this kind of information to deny insurancecoverage to carriers of the AT gene. A system that allows that type ofinformation to be used against people," he said, "is unfair. You don'tget to pick your genes; they shouldn't be used against you."
The co-authors in today's Science discovered a lot more than merelythe long-sought gene for AT. They found that the DNA sequence ofits non-mutated, healthy version, a 6-kilodalton transcript, some5,700 nucleotides long, has stretches that match up, unexpectedly,with known genes that govern the human cell cycle, and controlsensitivy to ultraviolet radiation and X-rays.
These homologies help explain AT's apparently open-endedconnection to many malignancies, and suggest double-edged medicalmeasures to mitigate such cancerous connections.
A Hypersensitivity To Radiation
One of the consortium's 30 co-authors, molecular biologistSankhavaram Patanjali of Yale University, explained to BioWorld:"two main features about ataxia" that arise from these similarsequences:
One is a probable hypersensitivity to radiation, because the ATmutant gene has a homology to a yeast gene, rad3, involved in correctcontrol of the cell cycle. When mutated, rad3 heightens radiationsensitivity.
The other is an enzyme, PI3 kinase, which seems to be implicated incontrol of cell growth, division and programmed death (apoptosis).
Both of these functions suggest to the researchers a direct cancer-causing connection. However, a spokesman for the National CancerInstitute, told the press conference, "there is no conclusive proof thatAT gene carriers are breast-cancer-prone."
"This gene is highly mutable," Shiloh said. "Of 50 patients we'vestudied so far, 43 have different mutations. This has implications forcreating diagnostic tools: You have to test for the whole gene. Itdoesn't mutate at the same point in the sequence. If there is a singlemutation," he observed, "that makes carrier identification mucheasier than if you have a mutable gene."
Test May Be Ready In Two Years
Collins pointed out that "It will take one or two years before we havethe technical ability to actually take a DNA sample and identify thegene misspellings quickly and cheaply."
He continued, however, "For families that already have an AT child,we could do it right now. If you have one affected person in thefamily, you can identify the mutation."
Apropos the prospect of gene therapy for AT, the human-genomeproject director said. "Gene therapy," Collins observed, "seems like anatural, because AT is due to a non-functioning copy of the gene.However, that is a very enormous challenge in this case, becausealthough it may be caused by a single gene, AT affects so manydifferent cells in the body _ brain, muscle, immune system, blood _it would be daunting to insert the healthy gene in all those cellsappropriately."
Collins perceives as "more promising, developing a designer drugthat could compensate for the malfunctioning of the gene."
Recently created knockout mice," he added, "would be crucialtoward developing such a drug."
In the week before Science published their report, Shiloh revealedthat Tel Aviv University received several phone calls from smallbiotech companies in the U.S. "They were primarily interested," hetold BioWorld Today, "in the way this gene may affect diseasescaused by cell-cycle defects, not so much in developing ATtherapies."
The university's dean and vice-president for research anddevelopment, Emmanuel Marom, added that the NIH and theuniversity have filed jointly for patent protection. He described theirpatent's claims as "broad," including the gene's DNA sequence and anumber of potential functions."
He added that no license agreements have been signed to date,despite last week's flurry of commercial interest.
Shiloh's next-stage game plan is "to complete cloning the gene,analyze its structure, look for the protein it encodes, and study theproblem of predisposition to cancer."
In this endeavor, he is taking samples from 1,000 American cancerpatients, trying to see if there is any connection between the AT genemutation and such predisposition." He will also study families withfamilial breast cancer "to see if the AT mutations increases risk ofbreast cancer."
And What About Mammograms
In this context, a disturbing _ though still decidedly hypothetical _catch-22 arises: AT carriers are unduly sensitive to X-radiation,presumably a prime instigator of malignancies. But mammary tumordetection relies heavily on periodic X-ray examination.
In 1991 Swift, of New York Medical College, found that womenfrom AT families who had breast cancer were far likelier to haveundergone X-ray mammography than those who hadn't. Moreover,X-radiation is frequently administered to treat many forms of cancer.
Collins' human genome research center, the National Cancer Instituteand the Danish Cancer Registry "are already planning to investigatethis disturbing potential," a Science editorial reported.
Meanwhile, Collins emphasized, "at the present time, it would bepremature for this information to be used to alter screeningrecommendations for mammography or other diagnostic procedures.n
-- David N. Leff Science Editor Lisa Piercey
(c) 1997 American Health Consultants. All rights reserved.