Hypoxanthine-guanine phosphoribosyltransferase deficiency in three brothers with gout: characterization of a variant, HPRTEdinburgh, having altered isoelectric point, increased thermal lability and normal levels of messenger RNA.

Three brothers who developed acute gouty arthritis at ages 16, 20 and 26 years were found to have increased plasma urate. Erythrocyte hypoxanthine phosphoribosyltransferase (HPRT) activity was less than 1% of normal and adenine phosphoribosyltransferase (APRT) activity was increased 2-3-fold. This variant, HPRTEdinburgh, was further studied using lymphoblast lines established from these patients and the following observations are consistent with a mutation involving a single amino acid substitution. Lymphoblasts from these patients had 0.9-1.6% of control HPRT activity which was 8-fold more labile than control activity at 75 degrees C. Isoelectric focusing of the variant protein in polyacrylamide gels indicated a pI of 6.5-6.7 which is more basic than normal HPRT, pI 6.0-6.3. The Michaelis constants were increased: 10-fold for hypoxanthine from 1.3 to 13 mumol/L, and 5-fold for PP-ribose-P from 6 to 30 mumol/L, for control and variant respectively. The Ki for product inhibition by GMP was marginally increased in the variant. Northern blot analysis of variant lymphoblast RNA indicated normal amounts of the expected 1.6 kilobase messenger RNA.