Scientists have found a variation that likely contributes to one in five cases of isolated cleft lip in a gene that had already been identified as playing a role in the formation of clefts.
This is the first time a genetic variant has been linked to cleft lip alone, rather than both cleft lip and palate.
The study, which 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., sheds light on a previously unknown genetic mechanism and could eventually help with diagnosis, prevention and treatment of cleft lip.
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.
For the study, researchers used computational and biological approaches. First, they used nonhuman DNA to predict potential regulatory sections around the gene in question.
Regulatory sections are separate from, but affect, the protein coding sections of genes. Regulatory sections are generally highly "conserved," meaning they have not changed much over evolution.
However, one of the regulatory sections around IRF6 revealed a single nucleotide variant, so the team focused on the corresponding area in human DNA already identified by a previous UI graduate student.
Next, the variant was shown to reside in a regulatory element that controls IRF6 expression. The team then studied large DNA collections on cleft lip and palate and found that among nearly 3,000 families those with cleft lip only were far more likely to have the genetic variant.
"It was most striking that this variant was associated with clefts of the lip only. We always thought that cleft lip alone and cleft lip with cleft palate were the same disease. Now we see a difference and will analyze patients with cleft lip separately from those who have both cleft lip and palate," Nature quoted 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.
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.
The findings appeared in Oct. 5 in the journal Nature Genetics.