GENETIC AND BIOCHEMICAL STUDY OF HUMAN CHROMOSOME 21

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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.