Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1978 Jan;75(1):482–485. doi: 10.1073/pnas.75.1.482

Evidence for X-linkage of human phosphoribosylpyrophosphate synthetase

Richard C K Yen 1, William B Adams 1, Cheri Lazar 1, Michael A Becker 1,*
PMCID: PMC411274  PMID: 203941

Abstract

The mode of genetic transmission of human phosphoribosylpyrophosphate synthetase (ribosephosphate pyrophosphokinase; ATP:D-ribose-5-phosphate pyrophosphotransferase; EC 2.7.6.1) was studied in fibroblasts cultured from members of a family with a structurally and electrophoretically altered phosphoribosylpyrophosphate synthetase that has increased activity per enzyme molecule. Enzyme activity in fibroblast lysates from the daughter of an affected male patient was intermediate to the activities in lysates from her father (and her affected paternal uncle) and from her mother and other normal individuals. Two bands of enzyme activity corresponding to normal and mutant phosphoribosylpyrophosphate synthetases were found in fibroblast lysates from the daughter after cellulose acetate strip electrophoresis. In contrast, only mutant enzyme was detectable in lysates derived from the male patients. Fibroblasts cloned from the daughter contained two phenotypically distinct (normal and mutant) populations of cells with respect to phosphoribosylpyrophosphate synthetase activity and electrophoretic mobility. These studies support assignment of the structural gene for human phosphoribosylpyrophosphate synthetase to the X-chromosome. No evidence for the presence of the normal enzyme was found in erythrocyte or lymphocyte lysates or in partially purified erythrocyte enzyme preparations from the heterozygous daughter, suggesting either nonrandom X-chromosome inactivation in precursors of these cells or selection against hematopoietic cells bearing the normal enzyme after random X-chromosome inactivation.

Keywords: genetic mapping, dosage compensation

Full text

PDF
482

Images in this article

484Image
on p.484

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Becker M. A., Kostel P. J., Meyer L. J. Human phosphoribosylpyrophosphate synthetase. Comparison of purified normal and mutant enzymes. J Biol Chem. 1975 Sep 10;250(17):6822–6830. [PubMed] [Google Scholar]
  2. Becker M. A., Kostel P. J., Meyer L. J., Seegmiller J. E. Human phosphoribosylpyrophosphate synthetase: increased enzyme specific activity in a family with gout and excessive purine synthesis. Proc Natl Acad Sci U S A. 1973 Oct;70(10):2749–2752. doi: 10.1073/pnas.70.10.2749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Becker M. A., Meyer L. J., Seegmiller J. E. Gout with purine overproduction due to increased phosphoribosylpyrophosphate synthetase activity. Am J Med. 1973 Aug;55(2):232–242. doi: 10.1016/0002-9343(73)90174-5. [DOI] [PubMed] [Google Scholar]
  4. Becker M. A., Meyer L. J., Wood A. W., Seegmiller J. E. Purine overproduction in man associated with increased phosphoribosylpyrophosphate synthetase activity. Science. 1973 Mar 16;179(4078):1123–1126. doi: 10.1126/science.179.4078.1123. [DOI] [PubMed] [Google Scholar]
  5. Becker M. A. Patterns of phosphoribosylpyrophosphate and ribose-5-phosphate concentration and generation in fibroblasts from patients with gout and purine overproduction. J Clin Invest. 1976 Feb;57(2):308–318. doi: 10.1172/JCI108282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. DAVIDSON R. G., NITOWSKY H. M., CHILDS B. DEMONSTRATION OF TWO POPULATIONS OF CELLS IN THE HUMAN FEMALE HETEROZYGOUS FOR GLUCOSE-6-PHOSPHATE DEHYDROGENASE VARIANTS. Proc Natl Acad Sci U S A. 1963 Sep;50:481–485. doi: 10.1073/pnas.50.3.481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Goss S. J., Harris H. New method for mapping genes in human chromosomes. Nature. 1975 Jun 26;255(5511):680–684. doi: 10.1038/255680a0. [DOI] [PubMed] [Google Scholar]
  8. Holmes E. W., McDonald J. A., McCord J. M., Wyngaarden J. B., Kelley W. N. Human glutamine phosphoribosylpyrophosphate amidotransferase. Kinetic and regulatory properties. J Biol Chem. 1973 Jan 10;248(1):144–150. [PubMed] [Google Scholar]
  9. Johnson M. G., Rosenweig S., Switzer R. L., Becker M. A., Seegmiller J. E. Evaluation of the role of 5-phosphoribosyl-alpha-1-pyrophosphate synthetase in congenital hyperuricemia and gout: a simple isotopic assay and an activity stain for the enzyme. Biochem Med. 1974 Jul;10(3):266–275. doi: 10.1016/0006-2944(74)90030-1. [DOI] [PubMed] [Google Scholar]
  10. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  11. LYON M. F. Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature. 1961 Apr 22;190:372–373. doi: 10.1038/190372a0. [DOI] [PubMed] [Google Scholar]
  12. Lebo R. V., Martin D. W., Jr An improved method for the electrophoretic separation and histochemical identification of 5-phosphoribosyl-1-pyrophosphate synthetase using microgram quantities of crude cell extracts. Adv Exp Med Biol. 1977;76A:570–574. doi: 10.1007/978-1-4613-4223-6_72. [DOI] [PubMed] [Google Scholar]
  13. Lyon M. F. Genetic activity of sex chromosomes in somatic cells of mammals. Philos Trans R Soc Lond B Biol Sci. 1970 Aug 6;259(828):41–52. doi: 10.1098/rstb.1970.0044. [DOI] [PubMed] [Google Scholar]
  14. Martin D. W., Jr, Maler B. A. Phosphoribosylpyrophosphate synthetase is elevated in fibroblasts from patients with the Lesch-Nyhan syndrome. Science. 1976 Jul 30;193(4251):408–411. doi: 10.1126/science.180603. [DOI] [PubMed] [Google Scholar]
  15. Mendelsohn J., Skinner A., Kornfeld S. The rapid induction by phytohemagglutinin of increased alpha-aminoisobutyric acid uptake by lymphocytes. J Clin Invest. 1971 Apr;50(4):818–826. doi: 10.1172/JCI106553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Migeon B. R., Der Kaloustian V. M., Nyhan W. L., Yough W. J., Childs B. X-linked hypoxanthine-guanine phosphoribosyl transferase deficiency: heterozygote has two clonal populations. Science. 1968 Apr 26;160(3826):425–427. doi: 10.1126/science.160.3826.425. [DOI] [PubMed] [Google Scholar]
  17. Nyhan W. L., Bakay B., Connor J. D., Marks J. F., Keele D. K. Hemizygous expression of glucose-6-phosphate dehydrogenase in erythrocytes of heterozygotes for the Lesch-Nyhan syndrome. Proc Natl Acad Sci U S A. 1970 Jan;65(1):214–218. doi: 10.1073/pnas.65.1.214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Romeo G., Migeon B. R. Genetic inactivation of the alpha-galactosidase locus in carriers of Fabry's disease. Science. 1970 Oct 9;170(3954):180–181. doi: 10.1126/science.170.3954.180. [DOI] [PubMed] [Google Scholar]
  19. Rosenbloom F. M., Henderson J. F., Caldwell I. C., Kelley W. N., Seegmiller J. E. Biochemical bases of accelerated purine biosynthesis de novo in human fibroblasts lacking hypoxanthine-guanine phosphoribosyltransferase. J Biol Chem. 1968 Mar 25;243(6):1166–1173. [PubMed] [Google Scholar]
  20. Sperling O., Boer P., Persky-Brosh S., Kanarek E., De Vries A. Altered kinetic property of erythrocyte phosphoribosylpsyrophosphate synthetase in excessive purine production. Rev Eur Etud Clin Biol. 1972 Aug-Sep;17(7):703–706. [PubMed] [Google Scholar]
  21. Sperling O., Eilam G., Sara-Persky-Brosh, De Vries A. Accelerated erythrocyte 5-phosphoribosyl-1-pyrophosphate synthesis. A familial abnormality associated with excessive uric acid production and gout. Biochem Med. 1972 Aug;6(4):310–316. doi: 10.1016/0006-2944(72)90017-8. [DOI] [PubMed] [Google Scholar]
  22. Thomas C. B., Arnold W. J., Kelley W. N. Human adenine phosphoribosyltransferase. Purification, subunit structure, and substrate specificity. J Biol Chem. 1973 Apr 10;248(7):2529–2535. [PubMed] [Google Scholar]
  23. Wada Y., Nishimura Y., Tanabu M., Yoshimura Y., Iinuma K. Hypouricemic, mentally retarded infant with a defect of 5-phosphoribosyl-1-pyrophosphate synthetase of erythrocytes. Tohoku J Exp Med. 1974 Jun;113(2):149–157. doi: 10.1620/tjem.113.149. [DOI] [PubMed] [Google Scholar]
  24. Zoref E., De Vries A., Sperling O. Mutant feedback-resistant phosphoribosylpyrophosphate synthetase associated with purine overproduction and gout. Phosphoribosylpyrophosphate and purine metabolism in cultured fibroblasts. J Clin Invest. 1975 Nov;56(5):1093–1099. doi: 10.1172/JCI108183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Zoref E., de Vries A., Sperling O. X-linked pattern of inheritance of gout due to mutant feedback-resistant phosphoribosylpyrophosphate synthetase. Adv Exp Med Biol. 1977;76A:287–292. doi: 10.1007/978-1-4613-4223-6_35. [DOI] [PubMed] [Google Scholar]
  26. de Vries A., Sperling O. Familial gouty malignant uric acid lithiasis due to mutant phosphoribosylpyrophosphate synthetase. Urologe A. 1973 Jul;12(4):153–157. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES