GENETIC AND BIOCHEMICAL STUDY OF HUMAN CHROMOSOME 21

唐氏综合征（21三体）是最常见的遗传性主要精神疾病的原因。 在美国的一个重要原因是先天性发育迟缓， 心脏病和自然流产。 唐氏综合症患者在 一般人群中发生的疾病风险增加， 白血病和老年痴呆症的早衰。 唐氏综合症 已经发现患者患有高尿酸血症，并且有证据表明， 这是由于嘌呤的过量产生。 我们已经证明 编码嘌呤生物合成的酶中的至少2种由以下编码： 21号染色体上的基因 我们净化了其中一个， 磷酸核糖基甘氨酸酰胺合成酶（加尔斯），从 并制备了抗鼠肝纤维化的抗体。 果蝇的加尔斯和磷酸核糖氨基咪唑基因 合成酶（AIRS）也在人类21号染色体上， 作为磷酸核糖基甘氨酸酰胺甲酰基转移酶基因的DNA序列 （GART）由S.赫尼科夫 我们现在建议1）确定是否 在唐氏综合征患者中观察到的升高的嘌呤水平与 这些基因在21号染色体上的存在和唐氏症的病理学 综合症，以及2）使用地点提供的独特遗传系统 嘌呤合成酶的基因， 21号染色体上致病区域的性质， 嘌呤合成与观察到的病理学直接相关。 具体 目的包括表征编码嘌呤合成的酶， 通过21号染色体上的基因以及基因的分离和表征 它们本身，确定嘌呤合成的速率是否变化 根据染色体21的内容，并创建一个详细的 21号染色体区域限制酶和物理连锁图谱 对唐氏综合症很重要，利用嘌呤酶的基因 综合作为起点。

Down Syndrome (Trisomy 21) is the most common genetic cause of major mental retardation in the United States and a significant cause of congenital heart disease and spontaneous abortion. Down syndrome individuals are at increased risk for diseases which occur in the general population such as leukemia and premature aging of the Alzheimer's type. Down Syndrome patients have been found to be hyperuricemic, and evidence indicating that this is due to purine overproduction has been obtained. We have shown that at least 2 of the enzymes coding for purine biosynthesis are coded for by genes on chromosome 21. We have purified one of these, phosphoribosylglycineamide synthetase (GARS), to apparent homogeneity from rat liver and prepared antibody to it. We have also shown that in Drosophila the genes for GARS and for phosphoribosylaminoimidazole synthetase (AIRS) also on chromosome 21 in humans, are on the same cloned DNA sequence as the gene for phosphoribosylglycineamide formyltransferase (GART) cloned by Dr. S. Henikoff. We now propose 1) to determine whether the elevated purine levels seen in Down syndrome patients are related to the presence of these genes on chromosome 21 and to the pathology of Down Syndrome, and 2) to use the unique genetic system afforded by the locations of the genes for enzymes of purine synthesis on chromosome 21 to understand the nature of the pathogenetic region on chromosome 21, whether or not purine synthesis is related directly to the observed pathology. Specific aims include characterization of the enzymes of purine synthesis coded for by genes on chromosome 21 and isolation and characterization of the genes themselves, determination of whether rate of purine synthesis varies according to chromosome 21 content, and the creation of a detailed retriction enzyme and physical linkage map of the region of chromsosome 21 important for Down Syndrome, using the genes for enzymes of purine synthesis as a starting point.