Lesch-Nyhan Disease: A Model for Complex Genetic, Proteomic & Metabolic Pathways

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Lesch Nyhan Disease (LND) represents an ideal model human disease in which to study the mechanisms by which even single gene defects produce very complex disruptions of normal genomic, proteomic, biochemical and metabolomic changes function. LND is a thoroughly characterized but poorly understood metabolic and neurobehavioral disorder characterized by metabolic and neurological dysfunction andcaused by mutations in the gene that encodesthe purine reutilization enzyme HPRT. Although much is known about the effects of HPRT deficiency on purine metabolism, there is little understanding of the mechanisms responsible for the complex disease phenotype. We therefore proposeto bring together the interests and expertise of a number of investigators at the University of California San Diego and Johns Hopkins University to undertake a broad systems networks and pathways approach to this disorder through the transoriptional, proteomic, biochemical developmental, metabolomic effects of HPRT deficiency in both the mammalian and the yeast model systems. The investigators included in this project have long individual histories of major advances to the problem of HPRT deficiency and to the development of technologies such as human proteome characterization, computational approaches to metabolomic studies and utilization of the yfeast model system for characterization of genetic aberrations in human disease. We shall unify these approaches nto a integrated program in an attempt to identify and understand the mechanisms that tie the purine defect to the complex HPRT deficiency disease phenotype. RELEVANCE (See instructions): Most human genetic and metabolic disease results from very complex interactions at the level of defective genes, abnormal proteins and altered metabolic processes. We propose to study that ways in which these omplex interacting factors cause the childhood neurological disorder Lesch Nyhan Disease.