Lesch-Nyhan Disease

In this area of research, we analyze the molecular basis of Lesch-Nyhan disease (LND). LND is a rare X-chromosomal disease caused by a defect of hypoxanthine phosphoribosyl transferase (HPRT). HPRT is a key enzyme of the purine salvage pathway. HPRT deficiency results in hyperuricemia, gouty arthritis and complex neuropsychiatric symptoms including self-injurious behavior, dystonia and mental retardation. However, it is not yet understood at the molecular level how HPRT deficiency translates into the neuropsychiatric phenotype. As a consequence of HPRT deficiency, abnormalities in the cellular concentrations of GTP, ATP, UTP and CTP result. In previous studies, our laboratory showed that GTP, UTP and CTP are functionally non-equivalent with respect to activation of G-proteins. Based on these findings, we put forward the hypothesis that abnormalities in G-protein-mediated signal transduction could provide the missing link between HPRT deficiency and the neuropsychiatric symptoms. While analyzing G-protein-mediated signal transduction in LND, we found, quite unexpectedly, that HPRT deficiency is associated with gross abnormalities in the activity of membrane low-affinity nucleoside 5’-triphosphatase (NTPase). Future studies in the laboratory aim at elucidating the molecular identity of the NTPase and its pathophysiological role. We will specifically address whether NTPases play a compensatory role to maintain relatively normal intracellular NTP concentrations in LND. In addition, we will study inasmuch as altered ectonucleotidase activity plays a role in purino- and pyrimidinoceptor-mediated signal transduction. Finally, we also plan to conduct gene array studies to identify altered gene expression in LND in a systematic fashion. As models for our studies, we use LND fibroblasts, various HPRT-deficient cell lines and HPRT knock-out mice. Our research is conducted in collaboration with Drs. H. Jinnah (Johns Hopkins University, MD, USA) and T. Friedmann and W. Nyhan (University of California at San Diego, CA, USA).

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