Study finds genetic variant plays role in...( University of Iowa researchers and ...)

University of Iowa researchers and collaborators have found, in a previously identified gene, a variation that likely contributes to one in five cases of isolated cleft lip. It is the first time a genetic variant has been associated with cleft lip alone, rather than both cleft lip and palate.

The study provides insight on a previously unknown genetic mechanism and could eventually help with diagnosis, prevention and treatment of cleft lip, which affects more than five million people worldwide. The findings appeared Oct. 5 in the journal Nature Genetics.

In 2004, a worldwide team involving the University of Iowa identified the gene IRF6 as a contributor to about 12 percent of cases of the common form of cleft lip and palate. The new finding pinpoints a regulatory part of the IRF6 gene that binds to a protein called AP2. This regulatory part controls how much and when the critical IRF6 protein is made.

The finding involved the lab of University of Iowa Carver College of Medicine faculty member Jeff Murray in collaboration with the University of Iowa lab of Frederick Domann, Ph.D., and adjunct faculty member Brian Schutte, Ph.D. Other investigators in Denmark, Norway, Scotland, Italy, the Philippines, California, and at the National Institutes of Health and the University of Pittsburgh were also critical to the investigation.

"We knew from the earlier study that IRF6 increases the risk of clefting. There are millions of common variants in the humane genome, but only a fraction have beneficial or harmful functions," said Fedik Rahimov, Ph.D., the lead author of the study and a graduate of the University of Iowa Interdisciplinary Program in Genetics, who worked in Murray's lab.

"We found that a common variant in the IRF6 gene severely disrupts the ability of AP2 to bind to it. This in turn disrupts proper expression of the IRF6 gene," said Rahimov, who is now a postdoctoral research fellow at Harvard Medical
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