Missing gene a potential risk factor for birth defects

03/31/04

Mouse embryos missing a gene that aids in the repair of DNA damage are at greater risk of developing birth defects, say University of Toronto scientists. The finding has implications for research into the cause of birth defects in humans.

The gene, also found in humans, produces an important protein called ATM which senses DNA damage caused by reactive oxygen species and directs other proteins to repair it. Reactive oxygen species are a normal product of the body's production of energy but can jump to toxic levels when cells are exposed to certain drugs, environmental chemicals and agents such as ionizing radiation.

In a study published online by the FASEB Journal in March, researchers at U of T's Leslie Dan Faculty of Pharmacy found that mice embryos genetically engineered to lack one or both copies of the ATM gene and then exposed to ionizing radiation and a subsequent overload of reactive oxygen species were at increased risk for dying in utero, developing birth defects or experiencing other developmental problems after birth. Because the mice lacked the protection of the ATM protein, these problems occurred even though the level of radiation was far below that which would normally affect a developing embryo.

"Although these pathways have not been investigated in the human embryo, these findings in mice provide new insights into how the embryo protects itself from oxidative stress and the associated risk factors for embryonic death and abnormal development," says senior author Professor Peter Wells. "This research provides evidence that the ATM gene protects embryos from birth defects initiated by DNA damage. In fact, when this gene is missing in mice, even without exposure to drugs, the normal physiological production of reactive oxygen species can be enough to damage the embryo. The next step is to see if this holds true for humans."

The prevalence of humans missing one copy of the ATM gene is relatively common, around one to two per cent of the population, says Wells. There is also a rare condition known as ataxia telangiectasia or AT in which people have no copies of the gene and are highly susceptible to problems such as neurological disorders and cancer.

Not much is known about why some children are more susceptible to birth defects than others, says Wells. If future research found that humans had the same sort of ATM sensitivity as mice, he says, it would suggest the potential for diagnostic tests to determine if an embryo is at risk for birth defects because it lacks the gene and even for possible protein therapies to help counteract ATM deficits in embryos.

"We want to see if the mechanisms that occur in mice will explain what occurs in humans or not," he says. "It's like a Las Vegas slot machine, in reverse. If all the bad lemons lined up if you had a lot of risk factors, such as no ATM gene combined with exposure to certain drugs and lack of other pathways that protect against reactive oxygen species you'd be in big trouble, according to our theory in mice. If it's only a few of the lemons, the risk for developing birth defects or dying in utero would be lower."

The study, by lead author and PhD candidate Rebecca Laposa, was funded by grants and a doctoral award from the Canadian Institutes of Health Research and by a Society of Toxicology fellowship. Other researchers involved in the study were pharmacy professor Jeffrey Henderson and undergraduate student Elaine Xu.

Source: Eurekalert & others

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