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.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Eleanor Roosevelt Institute for Cancer Research
United States
Zip Code
R├ęgnier, Vinciane; Billard, Jean-Marie; Gupta, Sapna et al. (2012) Brain phenotype of transgenic mice overexpressing cystathionine ?-synthase. PLoS One 7:e29056
Moat, Stuart; Carling, Rachel; Nix, Authur et al. (2010) Multicentre age-related reference intervals for cerebrospinal fluid serine concentrations: implications for the diagnosis and follow-up of serine biosynthesis disorders. Mol Genet Metab 101:149-52
Nielsen, Darci M; Evans, Jeffrey J; Derber, William J et al. (2009) Mouse model of fragile X syndrome: behavioral and hormonal response to stressors. Behav Neurosci 123:677-86
Knox, Aaron J; Graham, Christine; Bleskan, John et al. (2009) Mutations in the Chinese hamster ovary cell GART gene of de novo purine synthesis. Gene 429:23-30
Hoger, Joachim; Patterson, David; Hoger, Harald et al. (2009) Mice transgenic for reduced folate carrier: an animal model of Down syndrome? Amino Acids 36:349-57
Patterson, David; Graham, Christine; Cherian, Christina et al. (2008) A humanized mouse model for the reduced folate carrier. Mol Genet Metab 93:95-103
Pennington, Bruce F (2006) From single to multiple deficit models of developmental disorders. Cognition 101:385-413
Yao, Guimei; Chen, Xiao-Ning; Flores-Sarnat, Laura et al. (2006) Deletion of chromosome 21 disturbs human brain morphogenesis. Genet Med 8:1-7
Wenger, Galen R; Schmidt, Cecilia; Davisson, Muriel T (2004) Operant conditioning in the Ts65Dn mouse: learning. Behav Genet 34:105-19
Gardiner, Katheleen; Davisson, Muriel T; Crnic, Linda S (2004) Building protein interaction maps for Down's syndrome. Brief Funct Genomic Proteomic 3:142-56

Showing the most recent 10 out of 155 publications