This rare disorder is characterized by specific skin anomalies involving the neck and behind the ear, eye abnormalities, a typical facial appearance, and frequently cleft lip and palate. The study currently appears on-line in the April 17th issue of the American Journal of Human Genetics.

Using the latest in molecular microarray technologies, the researchers examined one affected mother and son and two sporadic BOFS cases and found a small deletion on chromosome 6 in the mother and son. Sequencing of genes in this candidate region revealed missense mutations clustered in the basic region of the DNA-binding domain of the TFAP2A gene in 4 sporadic BOFS patients.

According to lead author Jeff Milunsky, MD, director of clinical genetics, associate director of the Center for Human Genetics, and an associate professor of pediatrics, genetics and genomics at BUSM, this discovery will lead to more precise diagnostic testing, enable prenatal diagnosis, suggest directions for new research, and facilitate genetic counseling in these families. "This gene is a well-known transcription factor involved in multiple developmental pathways as well as tumorigenesis. An intriguing finding is that one of the affected patients with a mutation also has brain cancer, highlighting again the connection between malformations and cancer," he added. Milunsky believes this discovery may have significant wide-ranging implications as this gene may also play a role in the more common isolated occurrence of cleft lip and palate.

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The AlkB and ABH2 proteins repair alkylation damage to DNA, including the damage caused by alkylating cancer treatments. Alkylation is the addition of certain chemical groups to DNA and is particularly harmful to rapidly growing cells such as cancerous ones.

In an unexpected development last year, a team of European researchers published studies that identified an obesity gene in humans that belongs to the same family of proteins as AlkB. A defect in this gene, FTO, is associated with a weight gain of nearly seven pounds.

"It's surprising and exciting to see that the demethylation function is linked to obesity," He said. "Methylation is a type of alkylation that is used to regulate gene expression." One of his future goals is to determine the function of the FTO protein.

Among their many functions, proteins control chemical reactions in the cell by turning genes off and on. "This family of proteins might use demethylation as a signal to regulate gene activation," he said. "But this type of demethylation by AlkB and FTO has never been linked to gene activation in the past."

He oversees a research team of approximately 20 students and postdoctoral scientists, which occupies nearly half of one wing on the third floor of the Gordon Center for Integrative Science. The team collects most of its data at the Department of Energy's Advanced Photon Source at Argonne National Laboratory.

Over the course of many data-collection visits to Argonne, He's team has become well-acquainted with the scientists assigned to the lab's Structural Biology Center and BioCARS (Center for Advanced Radiation Sources). "After they learned of this work, they provided some new ideas that we're collaborating on," He said.

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