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Birth Defect Gene Found

Mouse mutation leads scientists to genetic clue for fatal neural tube defects

TUESDAY, Nov. 20, 2001 (HealthDayNews) -- British scientists have found a genetic clue to a birth defect so severe that afflicted fetuses are often miscarried or stillborn.

Researchers at London's Imperial College School of Medicine and Institute of Child Health have identified a genetic mutation in the mouse equivalent of the human birth defect called craniorachischisis, which affects the neural tube that develops into the brain and spinal cord.

They've also identified the human gene, which they hope could someday lead to therapies to correct such common neural tube defects (NTDs) as spina bifida. The findings appear in the Nov. 20 issue of Human Molecular Genetics.

The neural tube begins as a flat plate of cells that during normal growth folds down the center, with the two edges looping to form a tube. Normally, this tube seals, but a defect in this process can leave part or all of the tube unsealed.

In the most common of the neural tube defects, spina bifida, the lower end of the tube stays opens, leading to paralysis and disabilities and requiring corrective surgery. If the upper end of the tube near where the brain develops remains open, it leads to a fatal defect known as anencephaly.

In craniorachischisis, which makes up roughly 10 percent to 20 percent of the number of neural tube defects (NTDs), the entire neural tube remains open, causing miscarriage, stillbirth or death within days of birth. There is no known treatment.

Finding a genetic element has been difficult, says senior researcher Philip Stanier, because the defect appears to result from a combination of subtle genetic changes and environmental factors.

Because neural tube defects are hard to predict in humans, Stanier and his colleagues turned to a mouse model of craniorachischisis called the loop-tail or Lp mouse, which is prone to this NTD. Previous studies had focused the genetic search to chromosome 1, and using a process called positional cloning, Stanier's team narrowed the field to 12 potential genes involved in neural tube formation, eventually determining that the mutated Lpp1 mouse gene was their target.

"It's a gene that nobody really knows anything about," says Stanier.

"We always believed that there would be a human equivalent of this gene because the region we've mapped in the mouse DNA had a very similar region in the human," he adds. "To help find this [mouse] gene, we actually did a lot of work using the human genome sequence."

In fact, Stanier and his colleagues found the equivalent gene in humans first, although at the time they did not recognize its importance. The human gene, LPP1, is 99 percent similar to the mouse gene. The researchers are now investigating this gene in human cases of neural tube defects.

"It will be very interesting to see if it is a risk factor in humans, and ultimately, if we can develop some form of therapeutic prevention," says Stanier, although he says such a therapy may be years away.

Neural tube defects are one of the most common birth defects, affecting roughly one in 1,000 pregnancies. It is more prevalent, however, in northern China, Ireland and India's Sikh population, says Mary Seller, a professor of developmental genetics at King's College London.

"Neural tube defects are very complex," says Seller. "They don't follow logic -- you would expect them to be common in undernourished populations, but they aren't." She notes that the defects are less common in areas of Africa where the population would be considered malnourished.

However, says Seller, folic acid supplementation can reduce the risk of neural tube defects. Current dietary guidelines recommend that women trying to get pregnant should increase their intake of folic acid for one to three months before conception and throughout the pregnancy, since neural tube development occurs during the first trimester.

Although folic acid can be a preventive, the British researchers hope that their findings could ultimately lead to treatments for NTDs.

"We're going to learn a lot more about how this gene works," says Stanier. "With any luck, we will be able to find something that might be similar to folic acid, or some other type of compound, that will alleviate this."

What To Do

If you are considering becoming pregnant, speak to your doctor about how much folic acid should be in your diet.

Medline Plus is an excellent resource for information on neural tube defects.

Learn about prevention of neural tube defects from The Arc or check out these facts on folic acid from the Spina Bifida Association of America.

And here's some information on anencephaly from the National Institute of Neurological Disorders and Stroke.

SOURCES: Interviews with Philip Stanier, Ph.D., senior lecturer, Institute of Reproductive and Developmental Biology, Imperial College School of Medicine, London, U.K.; Mary J. Seller, D.Sc., Ph.D., professor of developmental genetics, King's College London, London, U.K.; Nov. 20, 2001, Human Molecular Genetics
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