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NIH Research Matters

September 29, 2006

Gene Plays Key Role in Cleft Lip and Palate

Several genes have been implicated in cleft lip and palate, one of the world's most common birth defects. Now, researchers have found that problems in a much-studied gene called SUMO1 can also cause cleft lip and palate. SUMO1 seems to play a key role in the network of proteins responsible for forming the palate, or roof of the mouth.

Picture of the SUM01 Gene in Human Chromosomes

The SUMO1 gene in human chromosomes. One copy shines bright (center arrowhead), but the other has been split by a chromosome rearrangement. This disruption can lead to cleft lip and palate. Image courtesy of Dr. Fowzan S Alkuraya, Genetics Division, Dept. of Medicine, Brigham and Women's Hospital and Harvard Medical School.

The discovery began several months ago when a clinician sent a blood sample to the laboratory of Dr. Richard Maas, a scientist at Brigham and Women's Hospital and Harvard Medical School. The sample came through an NIH-supported program called the Developmental Genome Anatomy Project, in which clinicians send laboratories samples from consenting patients with birth defects that appear to be caused by a particular type of chromosome rearrangement in which parts of two chromosomes switch places. The sample came from a five-year-old patient who had been born with a cleft lip and palate but no other obvious abnormalities.

The researchers, who were supported primarily by NIH's National Institute of Dental and Craniofacial Research and National Institute of General Medical Sciences, explain in the September 22 issue of the journal Science that the split gene in the patient's sample was the one for SUMO1, a small protein that the cell attaches to newly formed proteins to modify their function. Proteins modified this way are said to be "sumoylated." The researchers were intrigued, because at least three of the previously identified clefting genes are known to be sumoylated.

In developing mice, the team found, SUMO1 was produced in the region where the palate forms. Next, they ordered a stem cell line in which SUMO1 had been partially inactivated. It came from an NIH-supported consortium called BayGenomics, which has assembled a repository of mouse embryonic stem cells in which each line has a different gene inactivated. The researchers implanted the cells into female mice and found that four of 46 newborn mice had clefts of the palate or face—about the incidence of human families with a history of cleft lip and palate. When both SUMO1 and the sumoylated clefting gene Eya1 were inactivated, 36% of newborn mouse pups had clefts.

“The big challenge for research on cleft lip and palate is to move from studying individual genes to defining gene and protein networks,” Maas said. This discovery will allow researchers to begin connecting some of the dots and better understand the complex regulatory networks involved in forming the palate.

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Editor: Harrison Wein, Ph.D.
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NIH Research Matters is a weekly update of NIH research highlights from the Office of Communications and Public Liaison, Office of the Director, National Institutes of Health.

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This page last reviewed on December 4, 2012

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