Any week now, the Jackson Laboratory in Bar Harbor, Maine _ aleading purveyor of experimental animals _ will receive a fewhundred mice from the National Center for Human Genome Research(NCHGR), in Bethesda, Md.

Each of these small rodents is a living, breathing surrogate for manyif not most of the major ills that human flesh is heir to. During itsbrief life span _ two to four months rather than the 24 months ofnormal mouse expectancy _ the NCHGR knockout mouse manifestsa spectrum of disease states ranging from growth retardation,neurologic and immunologic dysfunction and infertility to themalignant thymic lymphoma that will eventually kill it in its prime.

These same disorders blight, and eventually take, the lives of one in40,000 to one in 100,000 young people worldwide. In the U.S., anestimated 500 children suffer from this rare, fatal inherited malady,which goes by the name of ataxia-telangiectasia (A-T).

A-T infants are born normal, but by two years or so of age they beginto become totterers instead of toddlers. (Ataxia means unsteady gait;lack of muscle coordination.)

Their speech slurs; their eyes move erratically; they areexcruciatingly sensitive to irradiation, strikingly prone to leukemiaand lymphoma, and recurrent respiratory infections. Some of theirsymptoms mimic multiple sclerosis and cystic fibrosis. Most A-Tchildren develop the telltale telangiectases _ dilated blood vessels ineye corners and face. Youngsters with A-T die in their teens or early20s.

A Boca Raton, Fla. businessman named Brad Margus who has twoyoung boys diagnosed with A-T is the founder of the "A-T Children'sProject."

Among researchers funded by the Project is molecular geneticist andcell biologist Yossef Shiloh of the University of Tel Aviv's ShacklerSchool of Medicine. Margus told BioWorld Today that it providesShiloh's A-T laboratory with an annual subsidy of $150,000.

That support paid off last summer when Shiloh cloned the ataxiatelangiectasis gene, Atm, which resides on human chromosome 11'slong arm. Among his collaborators was molecular biologist FrancisCollins, who became NCHGR's director in April 1993.

This long-sought cloning feat, in turn, made it possible for otherNCHGR scientists to construct a knockout mouse, lacking afunctional Atm gene, and thus capable of modeling the many andvaried pathological manifestations of A-T in human patients.

Collins and Shiloh are among the co-authors of a paper in today'sCell titled: "Atm-deficient mice: A paradigm of ataxiatelangiectasia." The article's senior author is clinical and moleculargeneticist Anthony Wynshaw-Boris, who heads the Mouse ModelsUnit at NCHGR's Laboratory of Genetic Disease Research.

"We had our first mice homozygous for the mutated A-T gene aroundthe first of this year," Wynshaw-Boris told BioWorld Today, andfrom that day to this we've been testing them for the differentmanifestations of A-T."

Over 100 mutations on the human Atm gene "have beencharacterized, and are either published or submitted for publication,"Wynshaw-Boris said. "It seems as though almost any mutation thatcauses a truncation of the ATM protein will disrupt the gene. Itsnormal function in the body, when intact, he added, "is thought to besomehow involved in sensing DNA damage, in repairing thatdamage, or in regulating cell-cycle progression in response to DNAdamage."

This near-ubiquitous genomic maintenance mission would helpexplain A-T's implication in so many disparate disorders, Wynshaw-Boris suggested, particularly in brain neurons, which control so manysystems in the body.

"That's really where the therapeutic potential is," he observed, "thatwe now have a model where first of all you can dissect the functionsof the gene, but second of all actually test compounds, and see ifthere's any improvement in the mice."

He continued: "Neurotrophic factors would be a very good possibilityfor testing brain survival, once we dissect a little bit more of thepathway in which the ATM gene product participates." HereWynshaw-Boris sees a connection with another ubiquitous protein,the p53 tumor suppressor.

"When normal cells are irradiated," he observed, "they increase p53levels. But irradiate A-T cells, and p53 does not increase. So it'spossible," he surmised, "that the p53 gene responds to the A-T signal.If so, maybe A-T patients _ and our mice _ are missing anappropriate p53 signal at certain times, and hence succumb to cancerssuch as thymic lymphoma."

Along these lines, he observed, "A lot of people are developing drugsthat would either increase or decrease p53 activity. These could betested on the mice. Once we understand the pathway a little more, notonly can we directly influence Atm levels, but maybe indirectlyinfluence its activity by working on other genes, for example p53,that may be more accessible to manipulation."

Wynshaw-Boris concluded: "You wouldn't have to try thesecompounds in the 500 human patients that are around, but test themin mice and see if there's any improvement."

That's where the Jackson Lab comes in. "Any academic orcommercial laboratory interested in studying cancer, infertility orbrain degeneration would be very interested in studying these mice,"Wynshaw-Boris said, and added: "Those mice are a model for ataxiatelangiectasis, but ataxia telangiectasis itself is a model for a lot ofother diseases. You're not just studying the fate of 500 kids." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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