PURINE SYNTHESIS, DOWN'S SYNDROME, AND MENTAL RETARDATION

嘌呤代谢缺陷导致嘌呤代谢增加或减少 在嘌呤生物合成中， 其他问题，包括自闭症，行为异常，感觉神经性 耳聋癫痫和痛风性关节炎 唐氏综合症患者 (DS)嘌呤代谢异常，导致150%的正常嘌呤 在他们的体液，和基因GART编码的多功能 进行嘌呤从头合成的3个步骤的蛋白质映射到 21号染色体。 在任何情况下，一种疾病的发病机制 由于已知的嘌呤代谢缺陷， 在DS患者中升高的嘌呤水平有任何其他 后果 细胞凋亡调控的分子遗传机制 嘌呤的合成尚未研究，也没有合适的动物模型 研究嘌呤的合成。 我们建议解决这些问题 1）评估分子遗传调控的作用， 细胞嘌呤合成，特别是GART的作用; 2）研究 卡斯基博士创造的一种新的尿酸酶缺陷小鼠的嘌呤合成 分析畸变对健康的影响， 3）使用部分16三体小鼠研究嘌呤合成 由Muriel Davisson博士建造，可能有一个额外的副本， 人GART表达载体的构建与分析 转基因小鼠的各种组合的后代的分析 上述2-4中研究的小鼠。 这些研究应该产生详细的 细胞和动物嘌呤调节机制的知识 合成，初步评估嘌呤的调节作用 在DS和其他形式的MR和发育疾病中的合成， 嘌呤代谢缺陷动物模型的建立 DS，并应确定是否异常嘌呤代谢发挥作用， 在建立DS表型中的重要作用。

Defects in purine metabolism resulting in either increases or decreases in purine biosynthesis lead to mental retardation (MR) and a variety of other problems, including autism, behavioral abnormalities, sensorineural deafness, epilepsy, and gouty arthritis. Individuals with Down Syndrome (DS) have abnormal purine metabolism leading to 150% of normal purines in their bodily fluids, and a gene GART encoding a multifunctional protein carrying out 3 of the steps of de novo purine synthesis maps to chromosome 21. In no case is the pathogenetic mechanism for a disease due to a defect in purine metabolism known, and it is not known whether the elevated purine levels in individuals with DS has any other consequences. Molecular genetic mechanisms of regulation of cellular purine synthesis have not been studied, and no suitable animal models exist for the study of purine synthesis. We propose to address these problems by 1) assessing the role of molecular genetic regulation of cellular purine synthesis and especially the role of GART; 2) Study of purine synthesis in a new uricase deficient mouse created by Dr. Caskey for analysis of the health-related effects of aberrations in this pathway; 3) Study of purine synthesis using a partial trisomy 16 mouse constructed by Dr. Muriel Davisson which may have an extra copy of the mouse GART gene; 4) Construction and analysis of human GART expressing transgenic mice; 5) Analysis of the offspring of various combinations of the mice studied in 2-4 above. These studies should generate detailed knowledge of mechanisms of regulation of cellular and animal purine synthesis, an initial assessment of the role of regulation of purine synthesis in DS and other forms of MR and developmental disease, establishment of an animal model to study purine metabolic defects and DS, and should determine whether aberrant purine metabolism plays a significant role in establishment of the DS phenotype.