Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Jul 15;98(2):352–357. doi: 10.1172/JCI118799

Mutations in exon 3 of the glycogen debranching enzyme gene are associated with glycogen storage disease type III that is differentially expressed in liver and muscle.

J Shen 1, Y Bao 1, H M Liu 1, P Lee 1, J V Leonard 1, Y T Chen 1
PMCID: PMC507437  PMID: 8755644

Abstract

Glycogen storage disease type HI (GSD-III), an autosomal recessive disease, is caused by deficient glycogen debranching enzyme (GDE) activity. Most GSD-III patients are GDE deficient in both liver and muscle (type IIIa), and some GSD-III patients have GDE absent in liver but retained in muscle (type IIIb). The molecular basis for this enzymatic variability is largely unknown. In the present study, the analysis of the GDE gene in three GSD-IIIb patients by single-strand conformation polymorphism (SSCP), DNA sequencing, restriction analysis, and family studies, revealed each of them as being a compound heterozygote for two different mutations. The first mutant alleles in all three patients involved mutations in exon 3 at amino acid codon 6 of the GDE protein. Two had an AG deletion at nucleotides 17 and 18 of the GDE cDNA (17delAG) which resulted in change of subsequent amino acid sequence and a truncated protein (25X); the other had a C to T transition at nucleotide 16 of the cDNA which changed a Glutamine codon to a stop codon (Q6X). The 17delAG mutation was also found in 8 of the 10 additional GSD-IIIb patients. The Q6X mutation was found in one of the remaining two GSD-IIIb patients. These two mutations were not found in any of the 31 GSD-IIIa patients, 2 GSD-IIId patients, nor 28 unrelated normal controls. The second mutant alleles in each of the three GSD-IIIb patients were R864X, R1228X, and W68OX. The R864X and R1228X were not unique for GSD-IIIb as they were also found in GSD-IIIa patients (frequency of 10.3% and 5.2% in Caucasian patients, respectively). Our data demonstrated that both IIIa and IIIb had mutations in the same GDE gene and established for the first time the molecular basis of GSD-III that differentially expressed in liver and muscle. The striking and specific association of exon 3 mutations with GSD-IIIb may provide insight into mechanisms controlling tissue-specific expression of the GDE gene. The identification of exon 3 mutations has clinical significance as well because it distinguished GSD-IIIb from IIIa hence permitting diagnosis from a blood sample rather than a more invasive muscle biopsy.

Full Text

The Full Text of this article is available as a PDF (195.3 KB).

Selected References

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

  1. Bates E. J., Heaton G. M., Taylor C., Kernohan J. C., Cohen P. Debranching enzyme from rabbit skeletal muscle; evidence for the location of two active centres on a single polypeptide chain. FEBS Lett. 1975 Oct 15;58(1):181–185. doi: 10.1016/0014-5793(75)80254-7. [DOI] [PubMed] [Google Scholar]
  2. Bell L. R., Maine E. M., Schedl P., Cline T. W. Sex-lethal, a Drosophila sex determination switch gene, exhibits sex-specific RNA splicing and sequence similarity to RNA binding proteins. Cell. 1988 Dec 23;55(6):1037–1046. doi: 10.1016/0092-8674(88)90248-6. [DOI] [PubMed] [Google Scholar]
  3. Bond R. W., Wyborski R. J., Gottlieb D. I. Developmentally regulated expression of an exon containing a stop codon in the gene for glutamic acid decarboxylase. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8771–8775. doi: 10.1073/pnas.87.22.8771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Coleman R. A., Winter H. S., Wolf B., Gilchrist J. M., Chen Y. T. Glycogen storage disease type III (glycogen debranching enzyme deficiency): correlation of biochemical defects with myopathy and cardiomyopathy. Ann Intern Med. 1992 Jun 1;116(11):896–900. doi: 10.7326/0003-4819-116-11-896. [DOI] [PubMed] [Google Scholar]
  5. Ding J. H., de Barsy T., Brown B. I., Coleman R. A., Chen Y. T. Immunoblot analyses of glycogen debranching enzyme in different subtypes of glycogen storage disease type III. J Pediatr. 1990 Jan;116(1):95–100. doi: 10.1016/s0022-3476(05)81652-x. [DOI] [PubMed] [Google Scholar]
  6. Gordon R. B., Brown D. H., Brown B. I. Preparation and properties of the glycogen-debranching enzyme from rabbit liver. Biochim Biophys Acta. 1972 Nov 10;289(1):97–107. doi: 10.1016/0005-2744(72)90112-x. [DOI] [PubMed] [Google Scholar]
  7. Gower H. J., Barton C. H., Elsom V. L., Thompson J., Moore S. E., Dickson G., Walsh F. S. Alternative splicing generates a secreted form of N-CAM in muscle and brain. Cell. 1988 Dec 23;55(6):955–964. doi: 10.1016/0092-8674(88)90241-3. [DOI] [PubMed] [Google Scholar]
  8. Kozak M. Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes. Cell. 1986 Jan 31;44(2):283–292. doi: 10.1016/0092-8674(86)90762-2. [DOI] [PubMed] [Google Scholar]
  9. Latchman D. S. Transcription-factor mutations and disease. N Engl J Med. 1996 Jan 4;334(1):28–33. doi: 10.1056/NEJM199601043340108. [DOI] [PubMed] [Google Scholar]
  10. Naeger L. K., Schoborg R. V., Zhao Q., Tullis G. E., Pintel D. J. Nonsense mutations inhibit splicing of MVM RNA in cis when they interrupt the reading frame of either exon of the final spliced product. Genes Dev. 1992 Jun;6(6):1107–1119. doi: 10.1101/gad.6.6.1107. [DOI] [PubMed] [Google Scholar]
  11. Taylor C., Cox A. J., Kernohan J. C., Cohen P. Debranching enzyme from rabbit skeletal muscle. Purification, properties and physiological role. Eur J Biochem. 1975 Feb 3;51(1):105–115. doi: 10.1111/j.1432-1033.1975.tb03911.x. [DOI] [PubMed] [Google Scholar]
  12. Terry M. J., Wahleithner J. A., Lagarias J. C. Biosynthesis of the plant photoreceptor phytochrome. Arch Biochem Biophys. 1993 Oct;306(1):1–15. doi: 10.1006/abbi.1993.1473. [DOI] [PubMed] [Google Scholar]
  13. Van Hoof F., Hers H. G. The subgroups of type 3 glycogenosis. Eur J Biochem. 1967 Oct;2(3):265–270. doi: 10.1111/j.1432-1033.1967.tb00134.x. [DOI] [PubMed] [Google Scholar]
  14. Yang-Feng T. L., Zheng K., Yu J., Yang B. Z., Chen Y. T., Kao F. T. Assignment of the human glycogen debrancher gene to chromosome 1p21. Genomics. 1992 Aug;13(4):931–934. doi: 10.1016/0888-7543(92)90003-b. [DOI] [PubMed] [Google Scholar]
  15. Yang B. Z., Ding J. H., Enghild J. J., Bao Y., Chen Y. T. Molecular cloning and nucleotide sequence of cDNA encoding human muscle glycogen debranching enzyme. J Biol Chem. 1992 May 5;267(13):9294–9299. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES