Deficiencies in different steps of
purine metabolism give rise to a number of human inherited disorders.
Lesch-Nyhan syndrome is a severe
neurological disorder, caused by a deficiency in the
purine salvage
enzyme hypoxanthine phosphoribosyltransferase (
HPRT).
HPRT-deficient mice have been generated, but have proved to be an unsuccessful model of the human disease. We have suggested that this may be due to a greater dependency in rodents on the other
purine salvage
enzyme,
adenine phosphoribosyltransferase (APRT). We have generated an APRT-deficient mouse line by gene targeting, with a phenotype that closely resembled the symptoms of
APRT deficiency in man. APRT null mice were viable, but 90% died prematurely before 6 months of age, displaying highly abnormal kidney morphology, with pathology characteristic of tubule obstruction. These mice have elevated urinary levels of
adenine and
2,8-dihydroxyadenine, a highly insoluble
adenine derivative, plus birefringent crystalline deposits and
calculi within tubules throughout the kidney. A standard
therapy for APRT-deficient human patients is the administration of the
xanthine oxidase inhibitor,
allopurinol. This has proved an effective
therapy for APRT null mice, preventing accumulation of
2,8-dihydroxyadenine and much of the resultant renal obstruction, allowing us to establish a breeding line. We believe that these mice should provide a useful model for further study of
APRT deficiency in humans. Furthermore, by generating APRT and
HPRT double mutants, we will be able to test our hypothesis that both genes must be inactivated in mice before a model for
Lesch-Nyhan syndrome can be obtained.