Scientists Spot Mutation Linked to Birth Defects

It's the first genetic link to neural tube defects such as spina bifida

WEDNESDAY, April 4, 2007 (HealthDay News) -- Canadian researchers say they have found the first genetic mutation clearly linked to neural tube birth defects such as spina bifida in humans.

"We have identified the mutations in a few patients with neural tube defects," said Philippe Gros, professor of biochemistry at McGill University in Montreal. "There are a total of 10 patients where we found the mutations. It is a very small number, but this is the first time that it has been pinned down."

The gene, designated VANGL1, codes for a protein that enables cells to orient themselves properly during development, Gros explained. A mutation causes cells to lose their orientation, so the tissue in which it is expressed fails to develop properly, causing gaps that leave nerve tissue exposed.

Gros's group first identified the mutation in mice. Now, reporting in the April 5 issue of the New England Journal of Medicine, they say they have found three VANGL1 mutations linked to neural tube defects in children treated at birth defect centers in Italy and France.

"There have been many association studies, some risk factors identified in certain genes, alterations in some genes associated with neural tube defects, but there hasn't been any clearly causative mutation," Gros said. "There hasn't been any situation like this, where you knock out the gene and find a neural defect in the mouse and then find the same thing in humans."

Yet VANGL1 is just one part of a large picture of neural tube defect causation, he said. "It is clearly a multigene situation. where alterations in more than one gene are responsible for the effect," Gros said.

"This is a very important finding that associates defects in this gene with neural tube defects in these specific families," said Marcy C. Speer, director of the Duke University Center for Human Genetics in Durham, N.C. "While only a few of the families looked at had the implicated variant, for those families, it is a very important finding."

Speer can appreciate the discovery, because she and her colleagues have been searching for such mutations without success so far. "We are looking at North Americans, have looked at about 30 to 50 genes, and haven't found any that appear to be a major risk factor," she said.

"There appears to be a combination of lots of different genes," she added. "In some populations, different genes may be more important, depending on what risk factors they are exposed to."

A major risk factor for neural tube defects is low levels of folic acid in the mother's diet, Speer noted. That's why folic acid supplements are now recommended before and during pregnancy. It is possible that some genetic variants play a role only in regions where dietary folate is low, Speer said.

As far as medical practice is concerned, "for therapy, we are not sure that it will have a great impact at this time," Gros said. "Scientifically, the discovery is fascinating, because the gene is found throughout the animal world, conserved all the way from flies to humans," he said.

The next step in the McGill research will be to investigate other proteins in which VANGL1 plays a role, to further pin down its mode of action, Gros said.

For Dr. Jennifer Wu, an obstetrician-gynecologist at Lenox Hill Hospital in New York, the discovery should be one more reminder of the need for folic acid supplements -- 400 milligrams a day is recommended -- for women contemplating pregnancy. "The neural tube is developing during the early days of pregnancy, and they should not miss out at that time," Wu said.

More information

There's more on neural tube defects at the Duke University Center for Human Genetics.

SOURCES: Philippe Gros, Ph.D., professor, biochemistry, McGill University, Montreal, Canada; Marcy C. Speer, Ph.D., director, Duke University Center for Human Genetics, Durham, N.C.; Jennifer Wu, M.D., obstetrican, Lenox Hill Hospital, New York; April 5, 2007, New England Journal of Medicine
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