Lesch Nyhan disease (LND) is a puzzling neurological developmental disorder caused by mutations in the gene encoding the purine salvage pathway enzyme hypoxanthine guanine phosphoribosyltransferase (HPRT). The disorder includes mental retardation, hyperuricemia, choreoathetosis and involuntary and compulsive self-mutilation. The role of deficient HPRT gene expression in the neurological phenotype is poorly understood, but is generally thought to be related to a reduction of dopamine content and dopamine uptake in the striatum. Very little is known regarding the mechanisms by which HPRT deficiency leads to the basal ganglion dopamine defects and to the neurological phenotype. In this exploratory application, the investigators propose to examine this central question by applying state-of-the-art screening of high density microarrays and DNA probe chips to identify genes and families of genes whose expression is affected by HPRT deficiency. Their proposed studies are based on evidence that: 1. the dopamine defect is causal in the neurological phenotype. 2. genes of purine metabolism, oxidative stress and expression of and response to neurotrophic factors are involved in the HPRT-dopamine interaction. 3. filter and chip array screening can identify individual genes and patterns of genes whose expression is modulated by HPRT expression.
