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Other entities represented in this entry:
SNOMEDCT: 237965005, 237966006; ORPHA: 364, 79259; DO: 0081331;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q23.3 | Glycogen storage disease Ic | 232240 | Autosomal recessive | 3 | SLC37A4 | 602671 |
A number sign (#) is used with this entry because of evidence that glycogen storage disease Ic (GSD1C) is caused by homozygous or compound heterozygous mutation in the G6PT1 gene (SLC37A4; 602671), which encodes glucose-6-phosphate translocase, on chromosome 11q23. G6PT1 is also the site of the defect in glycogen storage disease Ib (GSD1B; 232220).
Nordlie et al. (1983) reported studies of liver tissue from an 11-year-old girl with classic clinical features of type I glycogenosis. As in type Ib, glucose-6-phosphatase activity was lacking except in detergent-disrupted microsomes. Findings that differed from those of type Ib were interpreted on the basis of the multicomponent G6Pase system proposed by Arion et al. (1980). Defects in both T1, the translocase specific for G6P (deficient in type Ib), and T2, the putative translocase specific for Pi, PPi, and carbamyl-P, were thought to be involved. Burchell et al. (1987) described a second case of GSD type Ic in a 52-year-old man who had had no hypoglycemic symptoms. Glucose tolerance test showed impaired carbohydrate tolerance and glycosuria. These authors thought that only translocase T2 was defective. T1 is responsible for transport of glucose-6-phosphate into the endoplasmic reticulum, and T3 is responsible for transport of glucose out of the endoplasmic reticulum. Translocase T2 is concerned with transport of pyrophosphate into, and phosphate out of, the endoplasmic reticulum. The inability to transport phosphate means that, although glucose-6-phosphate can be taken into the lumen of the endoplasmic reticulum and hydrolyzed to glucose and phosphate, the phosphate cannot be removed from the lumen. Phosphate is an inhibitor of glucose-6-phosphatase activity. It is not surprising that there are multiple forms of type I GSD inasmuch as at least 5 different polypeptides are required for normal glucose-6-phosphatase activity in vivo (reviewed by Burchell, 1990). There are 3 transport proteins, termed T1, T2, and T3, which allow the substrates and products glucose-6-phosphate, phosphate (and pyrophosphate), and glucose to cross the endoplasmic reticulum membrane. Defects in the 3 transport proteins are referred to as types Ib, Ic, and Id glycogen storage disease, respectively. Burchell and Gibb (1991) reported experience with assays of 5 cases of GSD type Ib and 7 cases of GSD type Ic.
Visser et al. (1998) described a patient with GSD type Ic who suffered from neutropenia and neutrophil dysfunction as in GSD type Ib. Hypoglycemia had been noted in the neonatal period. At 3 months of age, hepatomegaly was noted combined with fasting intolerance, hyperlactic acidemia, and neutropenia. She suffered from recurrent infections of the upper respiratory tract and gastrointestinal tract from severe stomatitis. Recurrent neutropenia and disturbed neutrophil function were identified; furthermore, inflammatory bowel disease was confirmed by bowel radiography and bowel biopsy. At the age of 6 months, because of 12 infections in 6 months and continuous admission to hospital from the age of 4 months, treatment with granulocyte colony-stimulating factor (GCSF; 138970) was started. Thereafter the patient improved remarkably. Infection rate decreased dramatically and colonoscopy with bowel biopsies was normal. Studies of fresh liver tissues in this patient showed decreased enzyme activity in untreated homogenate, and higher activity in disruptive preparations, indicating a defect in 1 of the transporters, GSD Ib or GSD Ic. Further classification by investigation of the pyrophosphate phosphohydrolase showed that enzyme activity in the patient was decreased compared to controls, in untreated homogenates as well as in treated homogenates. This was considered compatible only with GSD Ic.
Gerin et al. (1997) cloned a cDNA encoding a putative glucose-6-phosphate translocase and found it to be mutated in 2 patients with GSD type Ib. GSD type Ib was mapped to 11q23 by Annabi et al. (1998) and GSD type Ic was mapped to 11q23-q24.2 by Fenske et al. (1998). Veiga-da-Cunha et al. (1998) showed that the gene encoding the putative translocase also maps to this region and demonstrated that the gene was mutated in 26 patients from a total of 22 families who had been diagnosed as either GSD type Ib or GSD type Ic.
Lin et al. (1999) studied the original patient with GSD Ic reported by Nordlie et al. (1983) and demonstrated that her G6PT gene was intact, suggesting that mutations in some other gene must be responsible. The GSD Ic disorder had been defined based on detailed kinetic analysis of the patient's G6Pase system. The index patient manifested neither neutropenia nor neutrophil/monocyte dysfunction, characteristic of GSD Ib. The GSD Ic patients identified by Veiga-da-Cunha et al. (1998) and Janecke et al. (1999) had been diagnosed solely on the basis of increased latency in hepatic microsomal inorganic pyrophosphatase activity, despite the fact that 3 patients also manifested neutropenia. The apparent discrepancy suggested to Lin et al. (1999) that GSD Ic cannot accurately be diagnosed by simply measuring inorganic pyrophosphatase activity in patients' hepatic microsomes. In fact, Nordlie et al. (1983) had shown that using G6P as a substrate, phosphate did not accumulate within the endoplasmic reticulum lumen of the original GSD Ic patient, suggesting pyrophosphate/phosphate transport comprises at least 2 proteins.
Annabi, B., Hiraiwa, H., Mansfield, B. C., Lei, K.-J., Ubagai, T., Polymeropoulos, M. H., Moses, S. W., Parvari, R., Hershkovitz, E., Mandel, H., Fryman, M., Chou, J. Y. The gene for glycogen-storage disease type 1b maps to chromosome 11q23. Am. J. Hum. Genet. 62: 400-405, 1998. [PubMed: 9463334] [Full Text: https://doi.org/10.1086/301727]
Arion, W. J., Lange, A. J., Walls, H. E., Ballas, L. M. Evidence for the participation of independent translocases for phosphate and glucose-6-phosphate in the microsomal glucose-6-phosphate system. J. Biol. Chem. 255: 10396-10406, 1980. [PubMed: 6253473]
Burchell, A. Molecular pathology of glucose-6-phosphatase. FASEB J. 4: 2978-2988, 1990. [PubMed: 2168325] [Full Text: https://doi.org/10.1096/fasebj.4.12.2168325]
Burchell, A., Gibb, L. Diagnosis of type 1B and 1C glycogen storage disease. J. Inherit. Metab. Dis. 14: 305-307, 1991. [PubMed: 1663192] [Full Text: https://doi.org/10.1007/BF01811688]
Burchell, A., Jung, R. T., Lang, C. C., Bennet, W., Shepherd, A. N. Diagnosis of type 1a and type 1c glycogen storage diseases in adults. Lancet 329: 1059-1062, 1987. Note: Originally Volume I. [PubMed: 2883397] [Full Text: https://doi.org/10.1016/s0140-6736(87)90484-3]
Fenske, C. D., Jeffery, S., Weber, J. L., Houlston, R. S., Leonard, J. V., Lee, P. J. Localisation of the gene for glycogen storage disease type 1c by homozygosity mapping to 11q. J. Med. Genet. 35: 269-272, 1998. [PubMed: 9598717] [Full Text: https://doi.org/10.1136/jmg.35.4.269]
Gerin, I., Veiga-da-Cunha, M., Achouri, Y., Collet, J.-F., Van Schaftingen, E. Sequence of a putative glucose 6-phosphate translocase, mutated in glycogen storage disease type Ib. FEBS Lett. 419: 235-238, 1997. [PubMed: 9428641] [Full Text: https://doi.org/10.1016/s0014-5793(97)01463-4]
Janecke, A. R., Bosshard, N. U., Mayatepek, E., Schulze, A., Gitzelmann, R., Burchell, A., Bartram, C. R., Janssen, B. Molecular diagnosis of type 1c glycogen storage disease. Hum. Genet. 104: 275-277, 1999. [PubMed: 10323254] [Full Text: https://doi.org/10.1007/s004390050948]
Lin, B., Hiraiwa, H., Pan, C.-J., Nordlie, R. C., Chou, J. Y. Type-1c glycogen storage disease is not caused by mutations in the glucose-6-phosphate transporter gene. Hum. Genet. 105: 515-517, 1999. [PubMed: 10598822] [Full Text: https://doi.org/10.1007/s004390051140]
Nordlie, R. C., Sukalski, K. A. Multiple forms of type I glycogen storage disease: underlying mechanisms. Trends Biochem. Sci. 11: 61-65, 1986.
Nordlie, R. C., Sukalski, K. A., Munoz, J. M., Baldwin, J. J. Type Ic, a novel glycogenosis: underlying mechanism. J. Biol. Chem. 258: 9739-9744, 1983. [PubMed: 6309784]
Veiga-da-Cunha, M., Gerin, I., Chen, Y.-T., de Barsy, T., de Lonlay, P., Dionisi-Vici, C., Fenske, C. D., Lee, P. J., Leonard, J. V., Maire, I., McConkie-Rosell, A., Schweitzer, S., Vikkula, M., Van Schaftingen, E. A gene on chromosome 11q23 coding for a putative glucose-6-phosphate translocase is mutated in glycogen-storage disease types Ib and Ic. Am. J. Hum. Genet. 63: 976-983, 1998. [PubMed: 9758626] [Full Text: https://doi.org/10.1086/302068]
Visser, G., Herwig, J., Rake, J. P., Niezen-Koning, K. E., Verhoeven, A. J., Smit, G. P. A. Neutropenia and neutrophil dysfunction in glycogen storage disease type 1c. J. Inherit. Metab. Dis. 21: 227-231, 1998. [PubMed: 9686363] [Full Text: https://doi.org/10.1023/a:1005399602020]