Discovery of Gene Variant for Cleft Lip

Jeffrey C. Murray, MD and Allen J. Wilcox, MD, Ph.D.
Department of Pediatrics, University of Iowa and NIEHS
NIEHS Grant P30ES005605

About one-fifth of isolated cleft lip may be due to a single nucleotide difference in the DNA sequence of a gene involved in facial development, according to new research findings from an international research team funded in-part by NIEHS and including an NIEHS intramural scientist. Isolated cleft lip, meaning the child has no other abnormalities, is one of the most common birth defects. The researchers say this discovery could lead to DNA tests to help couples better understand their risk of having a child with a cleft lip.

During fetal development, the lip normally fuses around 35 days of gestation. Since failure of lip fusion can impair the subsequent closure of the palatal shelves, cleft lip is often accompanied with cleft palate. If normally developed parents have a child with an isolated cleft lip, the risk of their second child having a similar cleft increases. Along with other recent gene discoveries, the research team reports they can now account for approximately 30 percent of isolated cleft lip. Just 25 years ago, there had yet to be a single gene identified.

This research finding began six years ago when the team discovered that a gene called IRF-6 is involved with a rare condition called Van der Woude syndrome. About 15 percent of people with the syndrome have malformations that are clinically indistinguishable from isolated cleft lip, which suggested that the gene might be involved in both conditions. Through studying the gene’s sequence they discovered a single sequence variant in a section of DNA that is almost identical across twelve different animals.

The team determined that the substitution of a single adenine molecule in place of a guanine in the IRF-6 gene alters the binding site for a protein called AP-2a. The protein is known to be involved in craniofacial development and when altered, causes a syndrome that involves clefts. These findings may not only lead to improvements in predicting clefts, but possibly better interventions to prevent them.

Citation: Rahimov F, Marazita ML, Visel A, Cooper ME, Hitchler MJ, Rubini M, Domann FE, Govil M, Christensen K, Bille C, Melbye M, Jugessur A, Lie RT, Wilcox AJ, Fitzpatrick DR, Green ED, Mossey PA, Little J, Steegers-Theunissen RP, Pennacchio LA, Schutte BC, Murray JC. Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip. Nat Genet. 2008 Nov;40(11):1341-7.