JAPANESE PATIENTS WITH PARTIAL APRT DEFICIENCIES ACCOMPANIED WITH 2,8-DIHYDROXYADENINE LITHIASIS SYNTHESIZE MUTANT APRT WITH ALTERED KINETIC PROPERTIES WHICH DOES NOT FUNCTION IN VIABLE CELLS: 98

Abstract

Although all Caucacian patients with 2,8-dihydroxyadenine urolithiasis completely lack adenine phosphoribosyltransferase (APRT), more than half of Japanese patients with the same lithiasis only partially lack APRT. The degrees of APRT deficiencies in these Japanese patients are broadly the same as healthy heterozygotes for complete APRT deficiencies. We found that cultured T-cells from the Japanese patients with partial APRT deficiencies were, like those from the patients with complete APRT deficiencies but unlike the heterozygotes, more than 100-fold less sensitive to adenine analogs, 6-methylpurine and 2,6-diaminopurine, suggesting that APRT of these Japanese patients is non-functional in viable cells, although it functions normally in test tubes. Therefore, it is not APRT activity in test tubes but whether APRT is functional in viable cells that is important for clinical symptoms (lithiasis). The mutant enzymes from four separate families were found to have reduced affinities to PRPP but not to adenine, and at physiological concentrations of PRPP, normal but not mutant enzymes showed significant activities. The mutant enzymes contained several other altered characteristics in common possibly suggesting that they are coded by a common mutant allele.