Hereditary Orotic Aciduria: Evidence for a Structural Gene Mutation

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Abstract
Orotic aciduria is a rare autosomal recessive disease in man due to a deficiency of orotate phosphoribosyltransferase (EC 2.4.2.10; orotidine-5'-phosphate:pyrophosphate phosphoribosyltransferase) and orotidine-5'-phosphate decarboxylase (EC 4.1.1.23; orotidine-5'-phosphate carboxy-lyase). We have compared certain physicochemical properties of orotidine-5'-phosphate decarboxylase from normal and mutant fibroblasts grown under identical conditions. Orotidine-5'-phosphate decarboxylase from homozygous mutant cells was more thermolabile and exhibited a different electrophoretic mobility when compared to the enzyme from normal cells; orotidine-5'-phosphate decarboxylase from one heterozygous cell strain exhibited an intermediate thermolability while the other heterozygote displayed a thermal inactivation curve indistinguishable from normal. The enzyme from both normal and mutant cells exhibited biphasic kinetics with the same apparent Michaelis constants. These data suggest that the molecular defect in the enzyme of this patient with orotic aciduria is due to a mutation in a gene that affects the structure of either orotate phosphoribosyltransferase or orotidine-5'-phosphate decarboxylase and cannot be attributed to a mutation in a regulatory gene, as previously suggested.