INBORN ERRORS OF A PURINE SALVAGE PATHWAY

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DESCRIPTION: Dr. Tischfield and his colleagues have been investigating the molecular and mutational basis for human adenine phosphoribosyl-transferase (APRT) deficiency, an autosomal recessive inborn error of purine metabolism, which produces 2,8-dihydroxyadenine (DHA) urolithiasis in the majority of recognized homozygotes. Per the aims of our last renewal application, we have produced gene-targeted, homozygous, APRT-deficient mice. These animals have very severe and early onset DHA renal lithiasis which leads to chronic renal failure and death in many animals. These observations, along with biochemical studies, indicate that the animals are a faithful clinical and genetic model of human APRT deficiency. The investigators propose to extend their very preliminary characterization of these mice in an effort to better understand APRT deficiency, purine metabolism, DHA renal lithiasis, urolithiasis in general, and, ultimately, chronic renal failure. They have also produced mice that are both APRT and HGPRT-deficient which do not appear to be a model for human Lesch-Nyhan syndrome. They propose to breed the mutant (targeted) APRT into different mouse strain backgrounds and quantitatively determine the extent of congenic strain specific differences in the nature or degree of urolithiasis. This will involve detailed morphological, histological, and biochemical analysis of mice of different ages. The therapeutic effects of allopurinol, hypoxanthine, and diet modifications will be evaluated. The investigators will also study and inhibit de novo purine biosynthesis in doubly deficient mice to better understand its relationship with purine salvage in normal and mutant animals. A study of DHA-induced gene expression in cultured kidney epithelial cells and whole kidneys is aimed at understanding molecular genetic processes that lead to nephrolithiasis and kidney failure.