Abstract
Glycogen storage disease (GSD) type 1, which is caused by the deficiency of glucose-6-phosphatase (G6Pase), is an autosomal recessive disease with heterogenous symptoms. Two models of G6Pase catalysis have been proposed to explain the observed heterogeneities. The translocase-catalytic unit model proposes that five GSD type 1 subgroups exist which correspond to defects in the G6Pase catalytic unit (1a), a stabilizing protein (1aSP), the glucose-6-P (1b), phosphate/pyrophosphate (1c), and glucose (1d) translocases. Conversely, the conformation-substrate-transport model suggests that G6Pase is a single multifunctional membrane channel protein possessing both catalytic and substrate (or product) transport activities. We have recently demonstrated that mutations in the G6Pase catalytic unit cause GSD type 1a. To elucidate whether mutations in the G6Pase gene are responsible for other GSD type 1 subgroups, we characterized the G6Pase gene of GSD type 1b, 1c, and 1aSP patients. Our results show that the G6Pase gene of GSD type 1b and 1c patients is normal, consistent with the translocase-catalytic unit model of G6Pase catalysis. However, a mutation in exon 2 that converts an Arg at codon 83 to a Cys (R83C) was identified in both G6Pase alleles of the type 1aSP patient. The R83C mutation was also demonstrated in one homozygous and five heterogenous GSD type 1a patients, indicating that type 1aSP is a misclassification of GSD type 1a. We have also analyzed the G6Pase gene of seven additional type 1a patients and uncovered two new mutations that cause GSD type 1a.
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- Arion W. J., Lange A. J., Walls H. E., Ballas L. M. Evidence for the participation of independent translocation for phosphate and glucose 6-phosphate in the microsomal glucose-6-phosphatase system. Interactions of the system with orthophosphate, inorganic pyrophosphate, and carbamyl phosphate. J Biol Chem. 1980 Nov 10;255(21):10396–10406. [PubMed] [Google Scholar]
- Beaudet A. L., Anderson D. C., Michels V. V., Arion W. J., Lange A. J. Neutropenia and impaired neutrophil migration in type IB glycogen storage disease. J Pediatr. 1980 Dec;97(6):906–910. doi: 10.1016/s0022-3476(80)80418-5. [DOI] [PubMed] [Google Scholar]
- Burchell A., Burchell B., Monaco M., Walls H. E., Arion W. J. Stabilization of glucose-6-phosphatase activity by a 21 000-dalton hepatic microsomal protein. Biochem J. 1985 Sep 1;230(2):489–495. doi: 10.1042/bj2300489. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Burchell A., Hume R., Burchell B. A new microtechnique for the analysis of the human hepatic microsomal glucose-6-phosphatase system. Clin Chim Acta. 1988 Apr 15;173(2):183–191. doi: 10.1016/0009-8981(88)90256-2. [DOI] [PubMed] [Google Scholar]
- Burchell A. Molecular pathology of glucose-6-phosphatase. FASEB J. 1990 Sep;4(12):2978–2988. doi: 10.1096/fasebj.4.12.2168325. [DOI] [PubMed] [Google Scholar]
- Burchell A., Waddell I. D. Diagnosis of a novel glycogen storage disease: type 1aSP. J Inherit Metab Dis. 1990;13(3):247–249. doi: 10.1007/BF01799362. [DOI] [PubMed] [Google Scholar]
- Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
- Gitzelmann R., Bosshard N. U. Defective neutrophil and monocyte functions in glycogen storage disease type Ib: a literature review. Eur J Pediatr. 1993;152 (Suppl 1):S33–S38. doi: 10.1007/BF02072085. [DOI] [PubMed] [Google Scholar]
- Klein P., Kanehisa M., DeLisi C. The detection and classification of membrane-spanning proteins. Biochim Biophys Acta. 1985 May 28;815(3):468–476. doi: 10.1016/0005-2736(85)90375-x. [DOI] [PubMed] [Google Scholar]
- Lange A. J., Arion W. J., Beaudet A. L. Type Ib glycogen storage disease is caused by a defect in the glucose-6-phosphate translocase of the microsomal glucose-6-phosphatase system. J Biol Chem. 1980 Sep 25;255(18):8381–8384. [PubMed] [Google Scholar]
- Lei K. J., Pan C. J., Shelly L. L., Liu J. L., Chou J. Y. Identification of mutations in the gene for glucose-6-phosphatase, the enzyme deficient in glycogen storage disease type 1a. J Clin Invest. 1994 May;93(5):1994–1999. doi: 10.1172/JCI117192. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lei K. J., Shelly L. L., Pan C. J., Sidbury J. B., Chou J. Y. Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a. Science. 1993 Oct 22;262(5133):580–583. doi: 10.1126/science.8211187. [DOI] [PubMed] [Google Scholar]
- Nordlie R. C., Sukalski K. A., Muñoz J. M., Baldwin J. J. Type Ic, a novel glycogenosis. Underlying mechanism. J Biol Chem. 1983 Aug 25;258(16):9739–9744. [PubMed] [Google Scholar]
- Schulze H. U., Nolte B., Kannler R. Evidence for changes in the conformational status of rat liver microsomal glucose-6-phosphate:phosphohydrolase during detergent-dependent membrane modification. Effect of p-mercuribenzoate and organomercurial agarose gel on glucose-6-phosphatase of native and detergent-modified microsomes. J Biol Chem. 1986 Dec 15;261(35):16571–16578. [PubMed] [Google Scholar]
- Speth M., Schulze H. U. The purification of a detergent-soluble glucose-6-phosphatase from rat liver. Eur J Biochem. 1992 Sep 15;208(3):643–650. doi: 10.1111/j.1432-1033.1992.tb17230.x. [DOI] [PubMed] [Google Scholar]
- Sukalski K. A., Nordlie R. C. Glucose-6-phosphatase: two concepts of membrane-function relationship. Adv Enzymol Relat Areas Mol Biol. 1989;62:93–117. doi: 10.1002/9780470123089.ch3. [DOI] [PubMed] [Google Scholar]
- Tasheva E. S., Roufa D. J. Deoxycytidine methylation and the origin of spontaneous transition mutations in mammalian cells. Somat Cell Mol Genet. 1993 May;19(3):275–283. doi: 10.1007/BF01233075. [DOI] [PubMed] [Google Scholar]