Nj. Redhead et al., MICE WITH ADENINE PHOSPHORIBOSYLTRANSFERASE DEFICIENCY DEVELOP FATAL 2,8-DIHYDROXYADENINE LITHIASIS, Human gene therapy, 7(13), 1996, pp. 1491-1502
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.