Researchers at Brigham and Women’s Hospital and Harvard Medical School, Boston, report in the Sept. 22 issue of the journal Science that a much-studied gene called "SUMO1," when underexpressed, can cause cleft lip and palate.
With several genes already implicated in causing cleft lip and palate, the authors noted that their addition to the list comes with a unique biological twist. The SUMO1 gene encodes a small protein that is attached to the protein products of at least three previously discovered "clefting" genes during facial development, in essence linking them into or near a shared regulatory pathway and now a hot spot for clefting.
"The big challenge for research on cleft lip and palate is to move from studying individual genes to defining individual protein networks," said Richard Maas, MD, PhD, a scientist and senior author on the report.
"By protein network, I mean a nexus of proteins that interact in a highly regulated way," he said. "It’s at this dynamic, real-time level that science will begin to see the big picture and tease out more of the needed insights to understand and hopefully eventually prevent cleft lip and palate in newborns.
"What’s exciting about SUMO1," Dr. Maas continued, "is it allows us for the first time to begin to connect at least some of the dots and hopefully lock into a highly informative protein network that feeds into additional protein networks to form the palate."
To determine whether SUMO1 is indeed a clefting gene, the researchers turned to their experimental model of choice, the mouse. After establishing that SUMO1 is expressed in the region of the developing mouse where the palate forms, the scientists asked themselves this question: what happens if SUMO1 is expressed at abnormally low levels as the palate forms?
They turned to a research consortium that uses so-called "knockout," or gene inactivation, technology for the systematic study of the individual genes with the mouse genome to decipher their possible functions. The researchers ordered the stem cell line in which SUMO1 had been partially inactivated, and they implanted the cells into female mice. Four of 46 newborn mice had clefts of the palate or face.
"That’s about the incidence that we see in human families with a history of cleft lip and palate," said Irfan Saadi, PhD, a co-lead author on the study and postdoctoral fellow. "So we weren’t put off by the low incidence at all. It’s what we would have expected."
The researchers also found that when SUMO1 and the sumoylated clefting gene Eya1 were both inactivated, clefting increased to 36 percent of newborn mouse pups, an indication that their proteins interact during palate development and a finding that additional experiments further confirmed.
The National Institute of Dental and Craniofacial Research, National Institutes of Health, and the National Institute of General Medical Sciences supported the research.
