Tetrahydrobiopterin deficiency and dopamine loss in a genetic mouse model of Lesch-Nyhan disease.

Hypoxanthine-guanine phosphoribosyltransferase (HPRT) is an enzyme that catalyses the conversion of hypoxanthine and guanine into their respective nucleotides. Inherited deficiency of the enzyme is associated with a loss of striatal dopamine in both mouse and man. Although HPRT is not directly involved in the metabolism of dopamine, it contributes to the supply of GTP, which is used in the first and rate-limiting step in the synthesis of tetrahydrobiopterin (BH4). Since BH4 is required as a cofactor for tyrosine hydroxylase in the synthesis of dopamine, any limitation in the supply of GTP could interfere with the synthesis of dopamine. The current studies were designed to address the hypothesis that the reduced striatal dopamine in mice with HPRT deficiency results from reduced availability of BH4. The mutant mice had small reductions in striatal BH4, with normal BH4 levels in other brain regions. Liver BH4 was normal in HPRT-deficient mutant mice, and a phenylalanine challenge test failed to reveal any evidence for impaired hepatic phenylalanine hydroxylase, another BH4-dependent enzyme. Although striatal BH4 content is not normal, supplementation with BH4 or L-dopa failed to correct the striatal dopamine deficiency of the mutant mice, suggesting that BH4 limitation is not responsible for the dopamine loss.