The Lesch-Nyhan (L-N) syndrome is an X-linked recessively inherited disease characterized by mental retardation, chorioathetosis, self-mutilative behavior and hyperuricemia. The disorder is genetically lethal, and since the affected males do not reproduce, it arises frequently by new mutation. We propose to study the molecular basis of new mutation in man by examining the types of mutation as well as the paternal gametic origin. The basis of the high level of hypoxanthine-guanine phosphoriboro-syltransferase (HPRT) expression is the central nervous system and the effect of its deficiency state (HPRT-) on neural development is unresolved. We propose to study both cell culture and transgenic mice in an effort to develop a model for L-N pathophysiologic studies. Finally, an attempt to develop HPRT- mice which correspond to the L-N disease of man will be made towards the objective of a model animal system for study and correction of the disease in man.
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