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.
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