MICE WITH ADENINE PHOSPHORIBOSYLTRANSFERASE DEFICIENCY DEVELOP FATAL 2,8-DIHYDROXYADENINE LITHIASIS

Deficiencies in different steps of purine metabolism give rise to a nu mber of human inherited disorders. Lesch-Nyhan syndrome is a severe ne urological disorder, caused by a deficiency in the purine salvage enzy me hypoxanthine phosphoribosyltransferase (HPRT). HPRT-deficient mice have been generated, but have proved to be an unsuccessful model of th e human disease. We have suggested that this may be due to a greater d ependency in rodents on the other purine salvage enzyme, adenine phosp horibosyltransferase (APRT). We have generated an APRT-deficient mouse line by gene targeting, with a phenotype that closely resembled the s ymptoms of APRT deficiency in man. APRT null mice were viable, but 90% died prematurely before 6 months of age, displaying highly abnormal k idney morphology, with pathology characteristic of tubule obstruction. These mice have elevated urinary levels of adenine and 2,8-dihydroxya denine, a highly insoluble adenine derivative, plus birefringent cryst alline deposits and calculi within tubules throughout the kidney. A st andard therapy for APRT-deficient human patients is the administration of the xanthine oxidase inhibitor, allopurinol. This has proved an ef fective therapy for APRT null mice, preventing accumulation of 2,8-dih ydroxyadenine and much of the resultant renal obstruction, allowing us to establish a breeding line. We believe that these mice should provi de a useful model for further study of APRT deficiency in humans. Furt hermore, by generating APRT and HPRT double mutants, we will be able t o test our hypothesis that both genes must be inactivated in mice befo re a model for Lesch-Nyhan syndrome can be obtained.