Digeorge Syndrome Gene Identified

New York, NY, March 6, 2001—Columbia researchers believe they have found the genetic basis for a common developmental disorder, DiGeorge syndrome, paving the way for future tests and perhaps treatments for the condition. DiGeorge syndrome affects about one in 4,000 live births. It produces defects of the heart and certain glands, and facial deformities, including an abnormally small jaw, cleft palate, and low-set ears. It is second only to Down syndrome as the most common developmental disorder to produce heart defects. The research was conducted by Loydie A. Jerome, a graduate student, and Virginia E. Papaioannou, Ph.D., professor of genetics and development. The results were published in the March 2 issue of the journal Nature Genetics. The Columbia researchers believe the disorder results from a mutation in which a gene, called TBX1, on chromosome 22 is absent. Mice lacking the mouse version of the same gene had developmental disorders strikingly similar to those in people with the syndrome. “We think we have pinned it down to a single gene,” said Dr. Papaioannou. Many researchers have been hunting for the disorder’s genetic basis for years and, before this finding, had narrowed the search down to a handful of genes. But it wasn’t clear which of them was implicated, nor whether one or several were responsible. The Columbia researchers were the first to identify one gene as principally responsible for the disorder. Their report is one of several papers published this week shedding light on the disorder’s genetic basis. These include papers in the March 1 issue of the journal Nature and the Feb. 23 issue of the journal Cell, based on research done at Baylor College of Medicine and Albert Einstein College of Medicine, respectively. Both these papers implicated TBX1 in the disease. But the Columbia paper was the first to show how the gene’s absence could produce all, --not only some--, of the abnormalities associated with the condition. Jerome and Dr. Papaioannou began studying DiGeorge syndrome while conducting more general investigations into a group of genes called T-box, of which TBX1 is one. T-Box is one of several families of genes called transcription factors, each of which acts as a “gateway” to a panoply of other genes. Transcription factors are like master switches that turn entire groups of other genes on and off. Other T-box genes have been implicated in developmental disorders. These including ulnar mammary syndrome, which can lead to deformations of the limbs and breast, and Holt-Oram syndrome, which causes abnormal hand and heart development. In studying how T-box genes function during embryonic development, the researchers found that TBX1 is activated in a part of the embryo that corresponds strikingly to where DiGeorge abnormalities develop. They hypothesized that this gene’s absence causes the condition. TBX1 is expressed in a region of the embryo, the head mesenchyme, which forms into the head and neck, and in an adjacent structure that becomes the thymus and parathyroid glands, which are also underdeveloped in DiGeorge syndrome. Another structure whose development depends on proper TBX1 expression is a part of the septum, tissue separating the heart’s outflow vessels, which is also defective in DiGeorge syndrome. “When you see a gene expressed (activated) in very specific areas of the embryo,” Dr. Papaioannou said, “you suspect it has something to do with the development of the tissues” formed in that area. The Columbia researchers studied the gene in mice, which are adequate subjects for gene research because more than 99 percent of their genes are held in common with people. They confirmed their suspicion when they bred mice lacking the gene in question and produced all the abnormalities associated with the disorder. But questions remain, Dr. Papaioannou said. In mice, the same gene must be knocked out of both sets of chromosomes to produce the full range of DiGeorge abnormalities. In most humans, only one chomosome needs to be affected for the same result. One subject of future research will be finding out why this happens. Dr. Papaioannou believes the reason is that the disorder is sensitive to an organism’s “background” genetic makeup. In other words, a range of other genes and their interactions may indirectly help determine how mild or severe a particular case is. “That’s one of the problems with getting to the core of the cause,” she said. What supports this contention, Dr. Papaioannou explained, is that the disorder is highly variable even in humans. Therefore, one strain of laboratory mice may be relatively insensitive to the disorder’s harmful effects and require the gene to be “knocked out” of both chromosomes before suffering the syndrome’s consequences. Other strains of mice may be more like humans and require just one chromosome knockout for the same result. Future research will probably involve studying the disorder in various strains of mice, Dr. Papaioannou said. The research was supported by the National Institutes of Health, the Raymond and Beverly Sackler Foundation and the National Science Foundation.

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