Researchers supported by the National Institutes of Health report in the current issue of the journal Science that a much-studied gene called SUMO1, when under expressed, can cause cleft lip and palate, one of the world’s most common birth defects.
With several genes already implicated in causing cleft lip and palate, the authors note 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 hotspot 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 Dr. Richard Maas, a scientist at Brigham and Women’s Hospital and Harvard Medical School and senior author on the paper. His research is supported by NIH’s National Institute of Dental and Craniofacial Research (NIDCR) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIGMS).
“By protein network, I mean a nexus of proteins that interact in a highly regulated way,” he continued. “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 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, or roof of the mouth.”
According to Maas, their discovery also offers a prime example of the power of genomic research, the comparative study of individual or sets of related genes among species, from yeast to human. The discovery also highlights the utility of comprehensive gene databases, DNA libraries, and other publicly accessible genomic resources to accelerate the pace of modern science.
Maas said the work that led to this weeks’s Science paper began several months ago when a clinician sent a blood sample from a five-year-old patient who had been born with a cleft lip and palate but no other obvious abnormalities. The sample arrived as part of an international program in which Maas’s lab participates, called the Developmental Genome Project, or DGAP.
To determine whether SUMO1 was indeed a clefting gene, the Maas lab 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 the next logical question: What happens if SUMO1 is expressed at abnormally low levels as the palate forms?
The scientists turned to a research consortium called BayGenomics that employs so-called “knockout,” or gene inactivation, technology to for the systematic study of the individual genes with the mouse genome to decipher their possible functions. The consortium, supported by NIH’s National Heart, Lung, and Blood Institute (NHLBI), has assembled a repository of embryonic stem cells for research purposes in which each available line has a different gene knocked out, or inactivated.
The Maas lab ordered the stem cell line in which SUMO1 had been partially inactivated, implanted them into female mice, and waited. The result: 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 Dr. Irfan Saadi, a co-lead author on the study and post-doctoral fellow in the Maas lab. “So we weren’t put off by the low incidence at all. It’s what we would have expected.”
NIDCR Office of Communications
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