Adenine phosphoribosyltransferase deficiency: a previously undescribed genetic defect in man William N. Kelley, … , J. Frank Henderson, J. Edwin Seegmiller J Clin Invest. 1968;47(10):2281-2289. https://doi.org/10.1172/JCI105913. Research Article A deficiency of adenine phosphoribosyltransferase (A-PRTase) is described in four members in three generations of one family. A-PRTase is coded by an autosome and the mutants described in this report are heterozygotes for this enzyme defect. The level of enzyme activity in these heterozygotes was inappropriately low, ranging from 21 to 37% of normal rather than the expected 50% of normal. Examination of various physical and chemical properties of the A-PRTase obtained from the mutant heterozygotes failed to reveal differences from the normal enzyme. These patients have no discernable abnormality in uric acid production despite the finding that patients with a deficiency of a closely related enzyme, hypoxanthine-guanine phosphoribosyltransferase, invariably produce excessive quantities of uric acid. A relationship of the A-PRTase deficiency to the disturbance in lipoprotein metabolism observed in the propositus has not been firmly established. Possible manifestations of the homozygous form of this enzyme deficiency will require identification of such individuals in the future. Find the latest version: https://jci.me/105913/pdf Adenine Phosphoribosyltransferase Deficiency: A Previously Undescribed Genetic Defect in Man WILLIAM N. KELLEY, ROBERT I. LEvy,' FREDEucK M. ROSENBLOOM, J. FANK HENDERSON, and J. EDWIN SEEGMILLER From the Section on Human Biochemical Genetics, National Institute of Arthritis and Metabolic Diseases and Laboratory of Molecular Diseases, National Heart Institute,* National Institutes of Health, Bethesda, Maryland 20014 A B ST R A CT A deficiency of adenine phospho- INTRODUCTION ribosyltransferase (A-PRTase) is described in A partial deficiency of an enzyme of purine me- four members in three generations of one family. tabolism, hypoxanthine-guanine phosphoribosyl- A-PRTase is coded by an autosome and the transferase (HG-PRTase) (Fig. 1), has recently mutants described in this report are heterozygotes been described in five patients with gout who for this enzyme defect. The level of enzyme activ- produce excessive quantities of uric acid (1). ity in these heterozygotes was inappropriately low, Subjects with a complete deficiency of this enzyme ranging from 21 to 37% of normal rather than also produce uric acid in excess but in addition the expected 50%o of normal. Examination of have a bizarre neurological and behavioral syn- various physical and chemical properties of the drome characterized by self-mutilation, choreo- A-PRTase obtained from the mutant heterozy- athetosis, spasticity, and mental deficiency (2). gotes failed to reveal differences from the normal These findings have suggested that the enzyme enzyme. These patients have no discernable ab- HG-PRTase is somehow concerned with the nor- normality in uric acid production despite the mal regulation of purine biosynthesis in man. finding that patients with a deficiency of a closely Genetic data based on biochemical (3) as well as related enzyme, hypoxanthine-guanine phospho- clinical studies (4-7) have established that the ribosyltransferase, invariably produce excessive gene for this enzyme is located on the X-chromo- quantities of uric acid. A relationship of the some. A-PRTase deficiency to the disturbance in lipo- In the present study a previously undescribed protein metabolism observed in the propositus has deficiency of a closely related enzyme, adenine not been firmly established. Possible manifesta- phosphoribosyltransferase (A-PRTase) (Fig. 1), tions of the homozygous form of this enzyme is reported in four members in three generations deficiency will require identification of such indi- of one family. Despite apparently close functional viduals in the future. similarity of this enzyme to HG-PRTase, its par- tial deficiency in these subjects is not associated This study was presented in part at the 60th Annual with excessive uric acid excretion. The propositus, Meeting of the American Society for Clinical Investiga- however, does have Type II hyperbetalipopro- tion, Atlantic City, N. J., 6 May 1968. (J. Clin. Invest. teinemia (8). From the limited genetic data 47: 53 a. 1968.) avail- Address reprint requests to Dr. Kelley. Present address: able in this kindred, the gene for A-PRTase Dept. of Medicine, Duke University Medical Center, appears to be located on an autosome rather than Durham, N. C. being X-linked and affected individuals may be Received for publication 19 April 1968. heterozygous for the defect, even though their The Journal of Clinical Investigation Volume 47 1968 2281 ADENINE PHOSPHORIBOSYLTRANSFERASE l H2 NH2 + PR PP rCNta H + PP HC.~ C H R-P Adenine Adenylic Acid HYPOXANTHINE-GUANINE PHOSPHORIBOSYLTRANSFERASE OH OH NC + PR PP II| CH + PP HN /C N/ H R-P Hypoxantkhin. Inosinic Acid OH OH + PRPP is \CH + PP H24CH IN vC H R-P Guanine Guanylic Acid FIGURE 1 Reactions catalyzed by the two enzymes, adenine phosphoribosyltransferase and hypoxanthine-guanine phosphoribosyltransferase. enzyme activity is substantially less than 50%o of rocyte A-PRTase activity was quite low despite normal. normal HG-PRTase activity, and he was admitted Case report. The propositus, E. H., a 45 yr old to the Clinical Center for further study. scientist (Ph.D.) and administrator, who has con- Clinical history revealed an asymptomatic pro- tinued to enjoy excellent health, first developed teinuria until age 18 and an episode of orchitis in arcus juvenilis at age 35. Serum cholesterol at that 1961 at the age of 39. There was no history of time was said to be elevated. In 1962 he began xanthomata, diabetes, or early death in the family. to develop nodules on both external pinnae. In His mother had a history a recurrent mild mono- 1967 a colleague felt that the lesions on his ears articular arthritis associated with mild hyper- might represent tophaceous deposits and a serum uricemia which had been diagnosed as gout. The urate was reported to be 7.2 mg/100 ml. Because patient has three daughters (Fig. 2) two of whom of this finding, he was referred to our service at (III-4 and III-5). are exceedingly bright, alert, the Clinical Center for further evaluation. The and healthy young ladies. A third daughter patient had no history suggestive of gouty arthritis (III-6), equally cooperative, has a mild cerebellar or nephrolithiasis, but a disorder of lipoprotein disorder attributed to an episode of encephalitis metabolism was suspected on the initial examina- which occurred at the age of 8 months. tion because of the presence of arcus and the his- Physical examination including detailed neuro- tory of a high cholesterol in the past. Erythrocytes logical and ophthalmological evaluation was nega- were obtained for determination of HG-PRTase tive except for the presence of bilateral arcus and A-PRTase as part of a control series being juvenilis. There were no xanthelasmata nor tendon obtained in our out-patient department. His eryth- or tuberous xanthomata. Hemogram, including 2282 Kelley, Levy, Rosenbloom, Henderson, and Seegmiller I l 2 , 3 4 5 6 2 3 4 5 6 7 8 9 * * Examined, Affected / Propositus 8l 0 Examined, Normal O 0 Not Examined FIGURE 2 "H" Family Pedigree, showing inheritance of adenine phosphoribo- syltransferase deficiency. hemoglobin, hematocrit, white blood cell count and METHODS differential, erythrocyte sedimentation rate, red A-PRTase and HG-PRTase activities were assayed in blood cell indexes, platelet count, and reticulo- dialysed lysates of washed erythrocytes by a radiochem- cytes, was normal. Renal function assessed by ical method described previously (1). The samples for excretion, enzyme assay obtained from the propositus, E. H., as urinalysis, timed phenolsulfonphthalein well as his wife and three daughters, were frozen im- blood urea nitrogen, and creatinine clearance was mediately without loss of enzyme activity. The samples normal. There was no proteinuria. Protein-bound on the remainder of the family were airmailed in ice iodine, 24 hr 131I uptake, thyroid scan, oral glucose from California, with 2 to 3 days intervening before the tolerance test, basal excretion of 17-hydroxycorti- samples could be frozen. This delay could have resulted in a loss of not more than 20% of the HG-PRTase and coids and 17-ketosteroids, and serum calcium and A-PRTase activities. Orotate phosphoribosyltransferase phosphorus concentrations revealed no evidence of (orotidylic pyrophosphorylase) was assayed in a simi- endocrine dysfunction. Liver function tests includ- lar manner using 0.6 mM orotic-6-'4C acid hydrate (3.5 ing alkaline phosphatase, serum glutamic oxala- mc/mmole) (New England Nuclear Corp. Boston, cetic transaminase, serum glutamic pyruvic trans- Mass.); 1 mm 5-phosphoribosyl-1-pyrophosphate (PRPP) (Pabst Research Laboratories Milwaukee, Wis.); 55 mM aminase, lactate dehydrogenase, thymol turbidity, Tris buffer, pH 7.4; 5 mm MgCl2; and 3-6 mg of he- and bilirubin were normal. There was, however, molysate protein in a final volume of 100 pl. After in- 10% retention of Bromsulfalein after 45 min. cubation for 3 hr at 38°C, the reactions were terminated Additional studies including protein electrophore- by the addition of 2 ,umoles of ethylenediaminetetraace- tate (EDTA) and immediately frozen in a dry ice sis, electrolytes (Na+, K+, Cl-, HCO3- and Mg++), acetone bath. 20 pi of the reaction mixture was placed acid phosphatase, lipase, amylase, ceruloplasmin, on 3MM Whatman paper with 0.06 ,umole of orotidylic copper, total serum iron, and VDRL were normal, (a gift of Dr. Herbert Windmueller) and uridylic acid, as were ECG and EEG. Audiometry revealed and the reaction products were separated from the sub- strate by high voltage electrophoresis in 0.05 M borate bilateral high tone hearing loss of the sensori- buffer, pH 9.0, containing 0.001 M EDTA at 4000 v for neural type. X-rays of the chest, axial skeleton, 30 min. The areas of the paper containing orotidylic and and large joints were unrevealing.