Alternative titles; symbols
HGNC Approved Gene Symbol: G6PC3
SNOMEDCT: 783058007;
Cytogenetic location: 17q21.31 Genomic coordinates (GRCh38) : 17:44,070,673-44,076,344 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.31 | Dursun syndrome | 612541 | Autosomal recessive | 3 |
| Neutropenia, severe congenital 4, autosomal recessive | 612541 | Autosomal recessive | 3 |
Glucose-6-phosphatase (G6Pase) is located in the endoplasmic reticulum (ER) and catalyzes hydrolysis of G6P to glucose and phosphate, the last step of the gluconeogenic and glycogenolytic pathways. G6PC3 is a ubiquitously expressed G6Pase catalytic subunit (Martin et al., 2002; Guionie et al., 2003).
By searching databases for homologs of IGRP (G6PC2; 608058), Martin et al. (2002) identified G6PC3, which they called UGRP. The predicted 346-amino acid protein has a calculated molecular mass of 38.7 kD and shares 36% and 37% identity with G6PC1 (232200) and IGRP, respectively. G6PC3 has 9 transmembrane domains and conserved G6Pase catalytic residues, but unlike G6PC1 and IGRP, it lacks N-linked glycosylation sites and the C-terminal KKxx motif characteristic of ER-resident transmembrane proteins. RNA blot analysis revealed ubiquitous expression of a 1.5-kb G6PC3 transcript. Expression was highest in skeletal muscle, intermediate in heart, brain, placenta, kidney, colon, thymus, spleen, and pancreas, and low in liver, lung, small intestine, and peripheral blood leukocytes.
By database analysis and RT-PCR of brain mRNA, Guionie et al. (2003) cloned human G6PC3.
Using Northern blot analysis, Cheung et al. (2007) found that G6PC3 was expressed in human blood neutrophils. RT-PCR showed that mouse leukocytes, neutrophils, and bone marrow expressed G6pc3 at similar levels.
Martin et al. (2002) determined that the G6PC3 gene contains 6 exons and spans 5.4 kb.
By genomic sequence analysis, Martin et al. (2002) mapped the G6PC3 gene to chromosome 17q21, where the G6PC1 gene is located.
Martin et al. (2002) found that transient transfection of COS-7 cells with human G6PC3 did not produce a significant change in G6P hydrolysis. Luciferase analysis showed that the G6PC3 promoter, unlike that of G6PC1, was highly active in all cell lines tested.
By stably expressing human G6PC3 in Chinese hamster ovary cells, Guionie et al. (2003) showed that G6PC3 had G6P hydrolysis activity. G6P hydrolysis by G6PC3 had a lower optimal pH and a higher Km relative to G6PC1, and G6PC3 preferentially hydrolyzed other substrates compared with G6PC1.
Using a combination of enzymologic, cell-culture, and in vivo approaches, Veiga-da-Cunha et al. (2019) demonstrated that G6PT (602671) and G6PC3 collaborate to destroy 1,5-anhydroglucitol-6-phosphate (1,5AG6P), a close structural analog of glucose-6-phosphate and an inhibitor of low-Km hexokinases, which catalyze the first step in glycolysis in most tissues. Veiga-da-Cunha et al. (2019) showed that 1,5AG6P is made by phosphorylation of 1,5-anhydroglucitol (1,5AG), a compound normally present in human plasma, by side activities of ADP-glucokinase and low-Km hexokinases.
In affected members of a large consanguineous Turkish family and an unrelated Turkish child with autosomal recessive severe congenital neutropenia (SCN4; 612541), Boztug et al. (2009) identified a homozygous mutation in the G6PC3 gene (611045.0001). In vitro functional expression assays showed that patient neutrophils carrying the mutation had increased susceptibility to apoptosis, although the oxidative burst was normal. Eight additional mutations (see, e.g., 611045.0002-611045.0005, 611045.0007) were identified in 7 other patients with the disorder.
In 1 of the Turkish children with Dursun syndrome (see 612541), Banka et al. (2010) identified a homozygous mutation in the G6PC3 gene (611045.0006). Each unaffected parent was heterozygous for the mutation, which was not found in 176 control chromosomes. The findings suggested that Dursun syndrome can be considered a subset of SCN4, with pulmonary hypertension as an important additional clinical feature.
Lin et al. (2015) reported that, at the time of their report, 33 separate G6PC3 mutations had been identified in G6PC3-deficient patients, but only the R253H (611045.0001) and G260R (611045.0007) missense mutations had been functionally characterized for pathogenicity. To demonstrate pathogenicity, Lin et al. (2015) functionally characterized 16 of the 19 known missense mutations using a sensitive assay based on a recombinant adenoviral vector-mediated expression system. Fourteen missense mutations completely abolished G6PC3 enzymatic activity, while 2 mutations retained 49% and 45%, respectively, of wildtype activity.
Wang et al. (2006) found that glucose-6-phosphatase hydrolytic activity was decreased by about 50% in brain homogenates from Ugrp-null mice compared to wildtype. Female, but not male, Ugrp-null mice had slightly decreased growth retardation. In contrast to G6pc1-null mice, Ugrp-null mice showed no change in hepatic glycogen content, blood glucose, or triglyceride levels compared to wildtype; however, female Ugrp-null mice showed increased plasma glucagon and reduced plasma cholesterol, suggesting that the hyperglucagonemia prevents hypoglycemia and that the decreased cholesterol was secondary to increased glucagon. Wang et al. (2006) concluded that the phenotype of Ugrp-null mice is mild, indicating that G6PC1 is the major glucose-6-phosphatase of physiologic importance.
Cheung et al. (2007) generated mice lacking G6pc3 and found that they were indistinguishable from wildtype mice and showed no disruption in glucose homeostasis. However, G6pc3 -/- mice were neutropenic and had defective neutrophil respiratory burst, chemotaxis, and calcium flux, as well as increased susceptibility to bacterial infection. G6pc3 -/- mice showed no impairment of hemopoiesis or granulocyte differentiation. Experimental peritonitis in G6pc3 -/- mice led to increased expression of glucose-regulated proteins upregulated during ER stress. G6pc3 -/- neutrophils also exhibited an enhanced rate of apoptosis. Cheung et al. (2007) concluded that inactivation of G6pc3 leads to neutrophil dysfunction that is most visible under conditions of immune stress, and that G6pc3 deficiency mimics the myeloid dysfunction of G6pt (G6PT1; 602671) -/- mice with glycogen storage disease Ib (232220).
McDermott et al. (2010) found that G6pc3-null mice had increased levels of mature neutrophils in the bone marrow despite reduced peripheral numbers of neutrophils, consistent with myelokathexis. Neutrophils from G6pc3-null mice had increased expression of Cxcr4 (162643), and treatment with a CXCR4 antagonist resulted in increased mobilization of neutrophils from the bone marrow. These findings suggested that high neutrophil expression of CXCR4 may contribute to neutropenia.
In affected members of a large consanguineous kindred from Turkey with severe congenital neutropenia (SCN4; 612541), Boztug et al. (2009) identified a homozygous 758G-A transition in exon 6 of the G6PC3 gene, resulting in an arg253-to-his (R253H) substitution in a highly conserved residue. The mutation was not identified in 192 controls. The patients had neonatal sepsis, intermittent thrombocytopenia, cardiac defects, and prominent superficial venous pattern. Bone marrow smears showed decreased mature neutrophils. Both peripheral neutrophils and skin fibroblasts from the patients showed an increased susceptibility to apoptosis, but the neutrophils showed normal oxidative burst. In vitro functional expression studies showed that the mutant R253H protein had no phosphatase activity. Electron microscopic studies showed an enlarged rough endoplasmic reticulum, consistent with increased stress.
In a large consanguineous kindred of Arab-Muslim descent in which 4 individuals had SCN4, Banka et al. (2011) identified a homozygous R253H mutation.
In a Turkish girl with severe congenital neutropenia (SCN4; 612541), Boztug et al. (2009) identified a homozygous 554T-C transition in the G6PC3 gene, resulting in a leu185-to-pro (L185P) substitution. She had pneumonia, sepsis, atrial septal defect, pulmonary valve stenosis, and prominent superficial venous pattern.
In a Greek girl with severe congenital neutropenia (SCN4; 612541), Boztug et al. (2009) identified a homozygous 141C-G transversion in the G6PC3 gene, resulting in a tyr47-to-ter (Y47X) substitution. She had perianal abscesses, recurrent urinary tract infections, inner-ear hearing loss, and prominent superficial venous pattern.
In a German girl with severe congenital neutropenia (SCN4; 612541), Boztug et al. (2009) identified a homozygous 778G-C transversion in the G6PC3 gene, resulting in a gly262-to-arg (G262R) substitution. She had omphalitis, recurrent urinary tract infections, an atrial septal defect, urachal fistula, microcephaly, prominent superficial venous pattern, and intermittent thrombocytopenia.
In an Iranian boy with severe congenital neutropenia (SCN4; 612541), Boztug et al. (2009) identified a homozygous 1-bp duplication (935dupT) in the G6PC3 gene, resulting in a frameshift and premature protein truncation. He had neonatal sepsis, an atrial septal defect, and patent ductus arteriosus.
In a Turkish child, born of nonconsanguineous parents, with pulmonary arterial hypertension, leukopenia, and atrial septal defect (see 612541), originally described by Dursun et al. (2009), Banka et al. (2010) identified a homozygous 346A-G transition in exon 3 of the G6PC3 gene, resulting in a met116-to-val (M116V) substitution in a highly conserved residue. Each unaffected parent was heterozygous for the mutation, which was not found in 176 control chromosomes. The child had a similarly affected sib, and both sibs died at age 18 months of severe respiratory distress due to primary pulmonary hypertension (PPH). Banka et al. (2010) noted that dysfunction of G6PC3 can result in defects in glucose metabolism, which may be associated with PPH.
In a German boy with severe congenital neutropenia-4 (SCN4; 612541), Boztug et al. (2009) identified a homozygous 778G-C transversion in the G6PC3 gene, resulting in a gly260-to-arg (G260R) substitution. Other features included growth retardation, type 2 atrial septal defect, cryptorchidism with genital dysplasia, microcephaly, inner-ear hearing loss, prominent superficial venous pattern, and intermittent thrombocytopenia.
McDermott et al. (2010) identified homozygosity for the G260R substitution in 2 sibs with SCN4 and multiple clinical abnormalities. The patients had a favorable response to G-CSF treatment, which resulted in increased peripheral neutrophil counts. The G260R mutation occurred in a conserved residue in the seventh transmembrane domain and caused a complete loss of enzyme activity. Bone marrow biopsies of both patients showed the presence of mature neutrophils despite markedly decreased neutrophils in the peripheral blood. The bone marrow also showed a predominance of atypical mononuclear megakaryocytes, myeloid hyperplasia, and vacuolization of the myeloid precursors. These features were consistent with myelokathexis and cytokine activation. Peripheral blood neutrophils and NK cells had increased expression of CXCR4 (162643), and G-CSF treatment resulted in a dose-dependent decrease of CXCR4. McDermott et al. (2010) concluded that the neutropenia in their patients resulted from a combination of decreased release of mature neutrophils from the bone marrow, increased apoptosis of peripheral blood neutrophils, and decreased superoxide production.
Banka, S., Chervinsky, E., Newman, W. G., Crow, Y. J., Yeganeh, S., Yacobovich, J., Donnai, D., Shalev, S. Further delineation of the phenotype of severe congenital neutropenia type 4 due to mutations in G6PC3. Europ. J. Hum. Genet. 19: 18-22, 2011. [PubMed: 20717171] [Full Text: https://doi.org/10.1038/ejhg.2010.136]
Banka, S., Newman, W. G., Ozgul, R. K., Dursun, A. Mutations in the G6PC3 gene cause Dursun syndrome. Am. J. Med. Genet. 152A: 2609-2611, 2010. [PubMed: 20799326] [Full Text: https://doi.org/10.1002/ajmg.a.33615]
Boztug, K., Appaswamy, G., Ashikov, A., Schaffer, A. A., Salzer, U., Diestelhorst, J., Germeshausen, M., Brandes, G., Lee-Gossler, J., Noyan, F., Gatzke, A.-K., Minkov, M., and 14 others. A syndrome with congenital neutropenia and mutations in G6PC3. New Eng. J. Med. 360: 32-43, 2009. Note: Erratum: New Eng. J. Med. 364: 1682 only, 2011. [PubMed: 19118303] [Full Text: https://doi.org/10.1056/NEJMoa0805051]
Cheung, Y. Y., Kim, S. Y., Yiu, W. H., Pan, C.-J., Jun, H.-S., Ruef, R. A., Lee, E. J., Westphal, H., Mansfield, B. C., Chou, J. Y. Impaired neutrophil activity and increased susceptibility to bacterial infection in mice lacking glucose-6-phosphatase-beta. J. Clin. Invest. 117: 784-793, 2007. [PubMed: 17318259] [Full Text: https://doi.org/10.1172/JCI30443]
Dursun, A., Ozgul, R. K., Soydas, A., Tugrul, T., Gurgey, A., Celiker, A., Barst, R. J., Knowles, J. A., Mahesh, M., Morse, J. H. Familial pulmonary arterial hypertension, leucopenia, and atrial septal defect: a probable new familial syndrome with multisystem involvement. Clin. Dysmorph. 18: 19-23, 2009. [PubMed: 19011569] [Full Text: https://doi.org/10.1097/MCD.0b013e32831841f7]
Guionie, O., Clottes, E., Stafford, K., Burchell, A. Identification and characterisation of a new human glucose-6-phosphatase isoform. FEBS Lett. 551: 159-164, 2003. [PubMed: 12965222] [Full Text: https://doi.org/10.1016/s0014-5793(03)00903-7]
Lin, S. R., Pan, C.-J., Mansfield, B. C., Chou, J. Y. Functional analysis of mutations in a severe congenital neutropenia syndrome caused by glucose-6-phosphatase-beta deficiency. Molec. Genet. Metab. 114: 41-45, 2015. [PubMed: 25492228] [Full Text: https://doi.org/10.1016/j.ymgme.2014.11.012]
Martin, C. C., Oeser, J. K., Svitek, C. A., Hunter, S. I., Hutton, J. C., O'Brien, R. M. Identification and characterization of a human cDNA and gene encoding a ubiquitously expressed glucose-6-phosphatase catalytic subunit-related protein. J. Molec. Endocr. 29: 205-222, 2002. [PubMed: 12370122] [Full Text: https://doi.org/10.1677/jme.0.0290205]
McDermott, D. H., De Ravin, S. S., Jun, H. S., Liu, Q., Long Priel, D. A., Noel, P., Takemoto, C. M., Ojode, T., Paul, S. M., Dunsmore, K. P., Hilligoss, D., Marquesen, M., Ulrick, J., Kuhns, D. B., Chou, J. Y., Malech, H. L., Murphy, P. M. Severe congenital neutropenia resulting from G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexis. Blood 116: 2793-2802, 2010. [PubMed: 20616219] [Full Text: https://doi.org/10.1182/blood-2010-01-265942]
Veiga-da-Cunha, M., Chevalier, N., Stephenne, X., Defour, J.-P., Paczia, N., Ferster, A., Achouri, Y., Dewulf, J. P., Linster, C. L., Bommer, G. T., Van Schaftingen, E. Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency. Proc. Nat. Acad. Sci. 116: 1241-1250, 2019. [PubMed: 30626647] [Full Text: https://doi.org/10.1073/pnas.1816143116]
Wang, Y., Oeser, J. K., Yang, C., Sarkar, S., Hackl, S. I., Hasty, A. H., McGuinness, O. P., Paradee, W., Hutton, J. C., Powell, D. R., O'Brien, R. M. Deletion of the gene encoding the ubiquitously expressed glucose-6-phosphatase catalytic subunit-related protein (UGRP)/glucose-6-phosphatase catalytic subunit-beta results in lowered plasma cholesterol and elevated glucagon. J. Biol. Chem. 281: 39982-39989, 2006. [PubMed: 17023421] [Full Text: https://doi.org/10.1074/jbc.M605858200]