Kelley-Seegmiller syndrome due to a unique variant of hypoxanthine-guaninephosphoribosyltransferase: reduced affinity for 5-phosphoribosyl-1-pyrophosphate manifested only at low, physiological substrate concentrations

A male child, who presented at the age of 3.5 years with acute renal failur e, was diagnosed as having partial deficiency of hypoxanthine-guanine phosp horibosyltransferase (HPRT; EC 2.4.2.8). The underlying HPRT mutation was u nique in that the specific activity of HPRT in erythrocyte and in fibroblas t lysates was normal, but the rate of uptake of hypoxanthine into nucleotid es of intact cultured fibroblasts was markedly reduced (23% of normal). The low functioning of HPRT in the intact fibroblasts was associated with decr eased utilization of endogenously generated hypoxanthine and with decreased utilization of the co substrate 5-phosphoribosyl-1-pyrophosphate (PRPP). T he non-utilized hypoxanthine was excreted into the incubation medium. The a ccumulation of PRPP was indicated by the 2.3-fold increase in the rate of u ptake of adenine into intact cell nucleotides and by the 7.5-fold enhanceme nt of the rate of de novo purine synthesis. Kinetic studies of HPRT activit y in fibroblast lysates revealed reduced affinity of the enzyme for PRPP (a pparent K-m 500 mu M in comparison to 25 mu M in control lysates), manifest ed in low activity at low (physiological), but not at high PRPP concentrati ons. The apparent K-m for hypoxanthine was normal (23 mu M in comparison to 14.2 mu M in control lysates). With allopurinol treatment, our patient has had no problems since presentation, and is developing normally at 5 years of age. (C) 2000 Elsevier Science B.V. All rights reserved.