azaguanine and Purine-Pyrimidine-Metabolism--Inborn-Errors

A family is reported where four males have developed hyperuricemia, renal damage and, except for the youngest person affected, gout at an early age. The disease appears to be inherited as an X-linked recessive metabolic error. Clinically the patients have developed classical, tophaceous gout before the age of 25 and have suffered repeated attacks of renal colic. Renal tubular damage with decreased ability to concentrate and acidify urine was seen in a family member of only 16 years of age. Progressive renal failure seems to develop slowly. None in the family has shown neurologic symptoms, and two of the four affected men are apparently of at least average intelligence, two slightly below average. One female carrier has repeatedly passed uric acid stones. Studies of the red blood cell lysate have shown a normal activity of enzyme hypoxanthine phosphoribosyltransferase, and an increased level of adenine phosphoribosyltransferase. Skin fibroblasts from affected family members grew normally in the presence of 8-azaguanine. Administration of azathioprine to the patients did not decrease their serum uric acid levels. This is the first family described with this type of disorder of the purine metabolism.

Topics: Adenine Phosphoribosyltransferase; Adolescent; Adult; Azaguanine; Azathioprine; Erythrocytes; Female; Fibroblasts; Genes, Recessive; Gout; Humans; Hypoxanthine Phosphoribosyltransferase; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Purine-Pyrimidine Metabolism, Inborn Errors; Uric Acid

For study of the basis of an X-linked form of gout in man, several clonal lines deficient in hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8) were selected from the human lymphoblast line WI-L2 by spontaneous and mutagen-induced resistance to 10 muM 8-azaguanine. Three groups could be defined: (1) clones with less than 1% of normal enzyme activity, unable to incorporate [(3)H]hypoxanthine detectable by radioautography, unable to tuilize exogenous hypoxanthine as a source of purines, and showing a 2- to 4-fold accelerated rate of production of early intermediates in de novo purine biosynthesis; (2) clones with 56-63% of normal enzyme activity, decreased incorporation per cell of [(3)H]hypoxanthine measured by radioautography, able to utilize exogenous hypoxanthine, and showing 1.2- to 2.8-fold purine overproduction; (3) clones with 10-15% of normal enzyme activity, able to utilize hypoxanthine but not incorporating amounts detectable by radioautography, and showing a 2.3- to 2.5-fold increase in purine biosynthesis. Resistant clones generated by ICR 191 mutagenesis resembled Group 1 clones. Heat inactivation studies in crude extracts from certain clones in Group 2 suggest a structural gene mutation, but no qualitative alteration in enzyme could be detected by starch gel electrophoresis. These phenotypes have persisted over at least 300 generations of nonselective growth, with retention of a diploid karyotype.

Topics: Autoradiography; Azaguanine; Cell Line; Clone Cells; Diploidy; Drug Resistance; Electrophoresis, Starch Gel; Genes; Genotype; Gout; Guanine; Humans; Hypoxanthines; Karyotyping; Mutation; Pentosyltransferases; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Spleen; Tritium

We have previously described a 14-yr-old boy with hyperuricemia, renal failure, and accelerated purine production resistant in vivo and in vitro to purine analogs. This patient demonstrated normal red cell hypoxanthine-guanine phosphoribosyltransferase (HPRT) heat stability, electrophoresis at high pH, and activity at standard substrate levels. In the present report an abnormal HPRT enzyme was demonstrated by enzyme kinetic study with phosphoribosylpyrophosphate (PRPP) as the variable substrate and inhibitory studies with sodium fluoride. Apparently normal HPRT activity in a patient with hyperuricemia and gout does not exclude a functionally significant HPRT mutation.

Topics: Adolescent; Aminopterin; Azaguanine; Azaserine; Cells, Cultured; Culture Media; Erythrocytes; Fibroblasts; Guanine; Humans; Hydrogen-Ion Concentration; Hypoxanthines; Kinetics; Lesch-Nyhan Syndrome; Male; Mutation; Organophosphorus Compounds; Pentosephosphates; Pentosyltransferases; Phosphoric Acids; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Temperature; Uric Acid

Topics: Athetosis; Autoradiography; Azaguanine; Biopsy; Compulsive Behavior; Culture Techniques; Female; Fibroblasts; Genetics, Medical; Humans; Huntington Disease; Hypoxanthines; Intellectual Disability; Lesch-Nyhan Syndrome; Mutation; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Self Mutilation; Skin; Uric Acid

Topics: Autoradiography; Azaguanine; Culture Techniques; Diploidy; Fibroblasts; Humans; Hypoxanthines; Male; Microscopy, Phase-Contrast; Models, Biological; Mutation; Purine-Pyrimidine Metabolism, Inborn Errors; Transferases; Tritium

Topics: Autoradiography; Azaguanine; Culture Techniques; Diploidy; Fibroblasts; Humans; Hypoxanthines; Male; Microscopy, Phase-Contrast; Models, Biological; Mutation; Purine-Pyrimidine Metabolism, Inborn Errors; Transferases; Tritium