鉴定了Digeorge综合征基因

2001年3月6日纽约2001年3月6日 - 哥伦比亚研究人员认为，他们认为他们已经找到了常见发育障碍，Digeorge综合征，为未来的测试铺平了遗传依据，也许是治疗方法。Digeorge综合征影响了4,000人的活产。它产生了心脏和某些腺体的缺陷，以及面部畸形，包括异常小的钳口，腭裂和低耳朵。它是仅次于唐氏综合征，作为产生心脏缺陷的最常见的发育障碍。该研究由Loydie A. Jerome，研究生和弗吉尼亚E.Papaioannou，Ph.D.，遗传学和发展教授。结果发表于3月2日问题杂志遗传学。哥伦比亚研究人员认为，不存在称为TBX1，染色体22的突变的突变是由突变产生的。缺乏同一基因的小鼠版本的小鼠具有与综合征的人的发育障碍相似。“我们认为我们已经把它固定在一个基因上，”Papaioannou博士说。许多研究人员多年来一直在狩猎这种疾病的遗传基础，并且在这一发现之前，已经将搜索缩小到少数基因。 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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