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Gene defect in Margarita islanders may protect against herpes infection
By Christina A. Pan

Colorado researchers have isolated a gene leading to cleft lip, one of the most common birth defects. They have also discovered that those carrying a single mutation of the gene may have a greater resistance to the herpes virus. The results of their study are published in the current issue of Nature Genetics.

"This is the first time we have found a gene for this birth defect and now know its biology," says Richard Spritz, of the University of Colorado Health Sciences Center in Denver.

Cleft lip, with or without cleft palate, is one of the many characteristics found in people with ectodermal dysplasia (ED), a genetic disorder affecting the development of skin, hair, nails, and glands. In this study, researchers examined extended families on Margarita Island, Venezuela. Settled by Christopher Columbus, Margarita is one of the oldest permanent Spanish colonies where a form of ED is indigenous. Margarita ED has similarities to other genetic disorders found in families in Israel and Brazil.

To pinpoint the gene, researchers first identified the chromosome linked to the development of facial and oral features. Then, using known genetic markers, they identified several genes; among them PVRL1, which is known to encode a protein receptor (nectin-1) involved in cell adhesion. It is also known that the herpes virus likes to hold onto nectin-1 while it gains entry into a cell.

defective gene inadvertently prevents herpes from infecting cells

To understand how nectin-1 is involved with the formation of facial and oral features, the researchers examined the embryos of developing mice. Nectin-1 was expressed during the development of the palate, toothbuds, and nasal cavity—areas that correspond with the physical abnormalities observed in the families affected by ED.

Upon further examination of the Margarita families, researchers found that some islanders possessed only one altered gene, making them carriers for the disorder while not expressing the abnormalities themselves. Spritz and his colleagues suspect that the high number of carriers on the island may have resulted from an acquired resistance to the herpes virus—a scenario that is similar to the acquired resistance to malaria, which is associated with carriers of the sickle-cell gene. ED carriers with the single mutation may be less likely to contract the herpes virus because defective PVRL1 inadvertently prevents herpes from infecting cells.

Spritz intends to study the cells from carriers to see if they are less susceptible to the herpes virus and to determine the importance of this revelation to normal cleft-palate development.

"Our goal is to study genes causing this disorder and be able to help identify people who are at high risk," says Spritz. "We are in the ballpark now and can continue to study the gene, and in particular, others like it to find out how they affect this aspect of human development. So far, initial results are promising."

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Suzuki, K. et al. Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia. Nat Gen 25, 427-430 (August 2000).

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