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. 1998 Aug 1;102(3):507–515. doi: 10.1172/JCI2890

Mutations in the liver glycogen synthase gene in children with hypoglycemia due to glycogen storage disease type 0.

M Orho 1, N U Bosshard 1, N R Buist 1, R Gitzelmann 1, A Aynsley-Green 1, P Blümel 1, M C Gannon 1, F Q Nuttall 1, L C Groop 1
PMCID: PMC508911  PMID: 9691087

Abstract

Glycogen storage disease type 0 (GSD-0) is a rare form of fasting hypoglycemia presenting in infancy or early childhood and accompanied by high blood ketones and low alanine and lactate concentrations. Although feeding relieves symptoms, it often results in postprandial hyperglycemia and hyperlactatemia. The glycogen synthase (GS) activity has been low or immeasurable in liver biopsies, whereas the liver glycogen content has been only moderately decreased. To investigate whether mutations in the liver GS gene (GYS2) on chromosome 12p12.2 were involved in GSD-0, we determined the exon-intron structure of the GYS2 gene and examined nine affected children from five families for linkage of GSD-0 to the GYS2 gene. Mutation screening of the 16 GYS2 exons was done by single-strand conformational polymorphism (SSCP) and direct sequencing. Liver GS deficiency was diagnosed from liver biopsies (GS activity and glycogen content). GS activity in the liver of the affected children was extremely low or nil, resulting in subnormal glycogen content. After suggestive linkage to the GYS2 gene had been established (LOD score = 2.9; P < 0.01), mutation screening revealed several different mutations in these families, including a premature stop codon in exon 5 (Arg246X), a 5'-donor splice site mutation in intron 6 (G+1T--> CT), and missense mutations Asn39Ser, Ala339Pro, His446Asp, Pro479Gln, Ser483Pro, and Met491Arg. Seven of the affected children carried mutations on both alleles. The mutations could not be found in 200 healthy persons. Expression of the mutated enzymes in COS7 cells indicated severely impaired GS activity. In conclusion, the results demonstrate that GSD-0 is caused by different mutations in the GYS2 gene.

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Selected References

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  1. Alonso M. D., Lomako J., Lomako W. M., Whelan W. J. A new look at the biogenesis of glycogen. FASEB J. 1995 Sep;9(12):1126–1137. doi: 10.1096/fasebj.9.12.7672505. [DOI] [PubMed] [Google Scholar]
  2. Aynsley-Green A., Williamson D. H., Gitzelmann R. Asymptomatic hepatic glycogen-synthetase deficiency. Lancet. 1978 Jan 21;1(8056):147–148. doi: 10.1016/s0140-6736(78)90442-7. [DOI] [PubMed] [Google Scholar]
  3. Aynsley-Green A., Williamson D. H., Gitzelmann R. Hepatic glycogen synthetase deficiency. Definition of syndrome from metabolic and enzyme studies on a 9-year-old girl. Arch Dis Child. 1977 Jul;52(7):573–579. doi: 10.1136/adc.52.7.573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Aynsley-Green A., Williamson D. H., Gitzelmann R. The dietary treatment of hepatic glycogen synthetase deficiency. Helv Paediatr Acta. 1977 Jun;32(1):71–75. [PubMed] [Google Scholar]
  5. Breathnach R., Chambon P. Organization and expression of eucaryotic split genes coding for proteins. Annu Rev Biochem. 1981;50:349–383. doi: 10.1146/annurev.bi.50.070181.002025. [DOI] [PubMed] [Google Scholar]
  6. Byrne B. M., Gillmer M. D., Turner R. C., Aynsley-Green A. Glucose homeostasis in adulthood and in pregnancy in a patient with hepatic glycogen synthetase deficiency. Br J Obstet Gynaecol. 1995 Nov;102(11):931–933. doi: 10.1111/j.1471-0528.1995.tb10886.x. [DOI] [PubMed] [Google Scholar]
  7. Cao Z., Umek R. M., McKnight S. L. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev. 1991 Sep;5(9):1538–1552. doi: 10.1101/gad.5.9.1538. [DOI] [PubMed] [Google Scholar]
  8. Darlington G. J., Wang N., Hanson R. W. C/EBP alpha: a critical regulator of genes governing integrative metabolic processes. Curr Opin Genet Dev. 1995 Oct;5(5):565–570. doi: 10.1016/0959-437x(95)80024-7. [DOI] [PubMed] [Google Scholar]
  9. Ercan N., Gannon M. C., Nuttall F. Q. Allosteric regulation of liver phosphorylase a: revisited under approximated physiological conditions. Arch Biochem Biophys. 1996 Apr 15;328(2):255–264. doi: 10.1006/abbi.1996.0171. [DOI] [PubMed] [Google Scholar]
  10. Furukawa K., Tagaya M., Tanizawa K., Fukui T. Role of the conserved Lys-X-Gly-Gly sequence at the ADP-glucose-binding site in Escherichia coli glycogen synthase. J Biol Chem. 1993 Nov 15;268(32):23837–23842. [PubMed] [Google Scholar]
  11. Gambino V., Menzel S., Trabb J. B., Xiang K. S., Lindner T., Louït A., Chen E., Mereu L. E., Furuta H., Iwasaki N. An approach for identifying simple sequence repeat DNA polymorphisms near cloned cDNAs and genes. Linkage studies of the islet amyloid polypeptide/amylin and liver glycogen synthase genes and NIDDM. Diabetes. 1996 Mar;45(3):291–294. doi: 10.2337/diab.45.3.291. [DOI] [PubMed] [Google Scholar]
  12. Gitzelmann R., Spycher M. A., Feil G., Müller J., Seilnacht B., Stahl M., Bosshard N. U. Liver glycogen synthase deficiency: a rarely diagnosed entity. Eur J Pediatr. 1996 Jul;155(7):561–567. doi: 10.1007/BF01957905. [DOI] [PubMed] [Google Scholar]
  13. KRISMAN C. R. A method for the colorimetric estimation of glycogen with iodine. Anal Biochem. 1962 Jul;4:17–23. doi: 10.1016/0003-2697(62)90014-3. [DOI] [PubMed] [Google Scholar]
  14. Kruglyak L., Daly M. J., Reeve-Daly M. P., Lander E. S. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet. 1996 Jun;58(6):1347–1363. [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. Landau B. R., Wahren J., Chandramouli V., Schumann W. C., Ekberg K., Kalhan S. C. Contributions of gluconeogenesis to glucose production in the fasted state. J Clin Invest. 1996 Jul 15;98(2):378–385. doi: 10.1172/JCI118803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Mahrenholz A. M., Wang Y. H., Roach P. J. Catalytic site of rabbit glycogen synthase isozymes. Identification of an active site lysine close to the amino terminus of the subunit. J Biol Chem. 1988 Aug 5;263(22):10561–10567. [PubMed] [Google Scholar]
  18. Mahtani M. M., Widén E., Lehto M., Thomas J., McCarthy M., Brayer J., Bryant B., Chan G., Daly M., Forsblom C. Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families. Nat Genet. 1996 Sep;14(1):90–94. doi: 10.1038/ng0996-90. [DOI] [PubMed] [Google Scholar]
  19. Nuttall F. Q., Gannon M. C. Allosteric regulation of glycogen synthase in liver. A physiological dilemma. J Biol Chem. 1993 Jun 25;268(18):13286–13290. [PubMed] [Google Scholar]
  20. Nuttall F. Q., Gannon M. C., Bai G., Lee E. Y. Primary structure of human liver glycogen synthase deduced by cDNA cloning. Arch Biochem Biophys. 1994 Jun;311(2):443–449. doi: 10.1006/abbi.1994.1260. [DOI] [PubMed] [Google Scholar]
  21. Nuttall F. Q., Gannon M. C., Kubic V. L., Hoyt K. J. The human liver Glycogen synthase isozyme gene is located on the short arm of chromosome 12. Genomics. 1994 Jan 15;19(2):404–405. doi: 10.1006/geno.1994.1086. [DOI] [PubMed] [Google Scholar]
  22. Nuttall F. Q., Gilboe D. P., Gannon M. C., Niewoehner C. B., Tan A. W. Regulation of glycogen synthesis in the liver. Am J Med. 1988 Nov 28;85(5A):77–85. doi: 10.1016/0002-9343(88)90400-7. [DOI] [PubMed] [Google Scholar]
  23. Orho M., Nikula-Ijäs P., Schalin-Jäntti C., Permutt M. A., Groop L. C. Isolation and characterization of the human muscle glycogen synthase gene. Diabetes. 1995 Sep;44(9):1099–1105. doi: 10.2337/diab.44.9.1099. [DOI] [PubMed] [Google Scholar]
  24. Orita M., Suzuki Y., Sekiya T., Hayashi K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics. 1989 Nov;5(4):874–879. doi: 10.1016/0888-7543(89)90129-8. [DOI] [PubMed] [Google Scholar]
  25. Petersen K. F., Laurent D., Rothman D. L., Cline G. W., Shulman G. I. Mechanism by which glucose and insulin inhibit net hepatic glycogenolysis in humans. J Clin Invest. 1998 Mar 15;101(6):1203–1209. doi: 10.1172/JCI579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rothman D. L., Magnusson I., Katz L. D., Shulman R. G., Shulman G. I. Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13C NMR. Science. 1991 Oct 25;254(5031):573–576. doi: 10.1126/science.1948033. [DOI] [PubMed] [Google Scholar]
  27. Sasaki K., Cripe T. P., Koch S. R., Andreone T. L., Petersen D. D., Beale E. G., Granner D. K. Multihormonal regulation of phosphoenolpyruvate carboxykinase gene transcription. The dominant role of insulin. J Biol Chem. 1984 Dec 25;259(24):15242–15251. [PubMed] [Google Scholar]
  28. Schalin-Jäntti C., Härkonen M., Groop L. C. Impaired activation of glycogen synthase in people at increased risk for developing NIDDM. Diabetes. 1992 May;41(5):598–604. doi: 10.2337/diab.41.5.598. [DOI] [PubMed] [Google Scholar]
  29. Tan A. W., Nuttall F. Q. Endogenous phosphates on liver glycogen synthase D and synthase I. Studies on the number and location. J Biol Chem. 1983 Aug 25;258(16):9624–9630. [PubMed] [Google Scholar]
  30. Wang N. D., Finegold M. J., Bradley A., Ou C. N., Abdelsayed S. V., Wilde M. D., Taylor L. R., Wilson D. R., Darlington G. J. Impaired energy homeostasis in C/EBP alpha knockout mice. Science. 1995 Aug 25;269(5227):1108–1112. doi: 10.1126/science.7652557. [DOI] [PubMed] [Google Scholar]
  31. Williams S. C., Cantwell C. A., Johnson P. F. A family of C/EBP-related proteins capable of forming covalently linked leucine zipper dimers in vitro. Genes Dev. 1991 Sep;5(9):1553–1567. doi: 10.1101/gad.5.9.1553. [DOI] [PubMed] [Google Scholar]

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