Gene offers new lead in cleft lip and palate research 21/9/06. By NIH/National Institute of Dental and Craniofacial Research The SUMO1 gene, when underexpressed, can cause cleft lip and palate, one of the world's most common birth defects.

A number of genes have been implicated in causing cleft lip and palate, but the new discovery comes with a 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 (Brigham and Women's Hospital and Harvard University Medical School in Cambridge, Mass.).

"By protein network, I mean a nexus of proteins that interact in a highly regulated way. 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."

Several months ago, 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 programme called the Developmental Genome Project, which relies on clinicians to send to DGAP-affiliated laboratories DNA samples from consenting patients with birth defects that appear to be caused by chromosome rearrangement, particularly so-called 'balanced translocations'. A balanced translocation means that during the normal cell cycle, two chromosomes stick together, break and form again incorrectly with parts of each chromosome switching places.

"DGAP builds on the hypothesis that the translocation splits a gene involved in the developmental process, renders it non functional and causes a visible birth defect," said Dr Fowan Alkuraya, a postdoctoral fellow in Maas's laboratory and co-lead author on the study. "In theory, the translocation will lead us to a biologically informative gene."

Alkuraya and colleagues found that the split gene in the patient's DNA sample encoded SUMO1, a small protein that is known to attach to the back of newly formed proteins to modify their function. "This was intriguing news because SUMO1 often attaches to or tags proteins to undergo a biochemical process called sumoylation, which influences their behaviour," said Maas. "At least three of the previously identified clefting genes are known to be sumoylated and, if SUMO1 turned out to be involved in clefting, it might lead us to a relevant protein network."

The scientists established that SUMO1 is expressed in the region of the developing mouse where the palate forms, and then found that inactivation of the gene led to clefts of the palate or face in four of 46 newborn mice. "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.

In additional work, the scientists found that when SUMO1 and the sumoylated clefting gene Eya1 were both inactivated, clefting increased to 36 per cent of newborn mouse pups, an indication that their proteins interact during palate development.

With more tools and data to sift through, Maas noted that the long held distinctions between syndromic and non-syndromic cleft lip and palate have begun to blur. Traditionally, 'syndromic' means babies are born with cleft lip and/or palate, in addition to other birth defects. 'Non-syndromic' refers to newborns who have cleft lip and/or palate only.

"Clefting reflects the combined actions of multiple gene products, rarely only one gene and its protein," said Maas. "That's why it's likely that what we now call non-syndromic has a very heterogenous mixture of manifestations too. It's just that the other manifestations are so subtle or not immediately obvious that we don't recognise them. Through our work and that of our colleagues, we can begin to better define these conditions."

Adapted from a news release by NIH/National Institute of Dental and Craniofacial Research .

Above image credit
Median cleft-lip proper in child. Courtesy of the Wellcome Trust Medical Photographic Library , London.

References

Alkuraya FS, et al. SUMO1 haploinsufficiency leads to cleft lip and palate . Science. 2006 Sep 22;313(5794):1751.