Elevated UTP and CTP content in cultured neurons from HPRT-deficient transgenic mice

Hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8.; HPRT) catalyze s the salvage synthesis of inosine-5'-monophosphate (IMP) and guanosine-5'- monophosphate (GMP) from the purine bases hypoxanthine and guanine, respect ively. Complete deficiency of HPRT activity is associated with the Lesch-Ny han syndrome (LNS), characterized by excessive purine production and severe neurological manifestations. The etiology of the metabolic consequences of HPRT deficiency is clarified, but that of the neurological manifestations is not yet understood. HPRT-deficient mice represent an experimental animal model of LNS. In search for a possible metabolic abnormality in LNS brains , connecting the neurological deficit to HPRT deficiency, the purine and py rimidine nucleotide content of cultured neurons, prepared from HPRT-deficie nt transgenic mice, was now determined. The HPRT-deficient neuronal culture s exhibited a significantly elevated content of the pyrimidine nucleotides UTP (1.33-fold the normal level, p = 0.0002) and CTP (1.28-fold the normal level, p = 0.02), but normal content of the purine nucleotides ATP and GTP. This abnormality in neuronal pyrimidine nucleotide content may be associat ed with the pathophysiology of the neurological deficit in LNS.