Diminished Affinity for Purine Substrates as a Basis for Gout with Mild Deficiency of Hypoxanthine-Guanine Phosphoribosyltransferase

Abstract

Deficiency of HGPRT activity is a well-established cause of excessive purine nucleotide and uric acid production. Nevertheless, only a very small proportion of patients with gout or uric-acid stone formation are deficient in this enzyme and, in these patients residual enzyme activity is less than 30% of normal activity (1,2,3). Since routine screening of HGPRT activity has usually been restricted to measurement of the maximal rate of the enzyme reaction determined at saturating substrate concentrations, the possibility remains that significant numbers of patients with functional deficiencies in HGPRT activity exist in whom the enzyme abnormality is minimally, or not at all, expressed as a diminished maximal reaction velocity. The present study, in which HGPRT activity was measured at subsaturating substrate concentrations, was undertaken in order to assess the frequency of occurrence of such variants of HGPRT deficiency. These studies confirm the occurrence of functionally important HGPRT deficiencies which are poorly reflected in the routine screening procedures, and indicate that mutation in substrate binding to the enzyme, though rare, is a definite mechanism of HGPRT deficiency.