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G6PC3

MIM.611045 17q21

Sunday 29 March 2009

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.

Pathology

- germline mutations of G6PC3 in

Physiopathology

Defective function of glucose-6-phosphatase, catalytic subunit 3, underlies a severe congenital neutropenia syndrome associated with cardiac and urogenital malformations.

Patients are susceptible to bacterial infections and had very few mature neutrophils in the bone marrow; structural heart defects, urogenital abnormalities, and venous angiectasia on the trunk and extremities were additional features.

Sequencing of G6PC3, the candidate gene encoding glucose-6-phosphatase, catalytic subunit 3, revealed a homozygous missense mutation in exon 6 that abolished the enzymatic activity of glucose-6-phosphatase in all affected children in the two families.

The patients’ neutrophils and fibroblasts had increased susceptibility to apoptosis.

The myeloid cells showed evidence of increased endoplasmic reticulum stress and increased activity of glycogen synthase kinase 3beta (GSK-3beta).

The main features of severe congenital neutropenia are the onset of severe bacterial infections early in life, a paucity of mature neutrophils, and an increased risk of leukemia.

References

- Mutations in the G6PC3 gene cause Dursun syndrome. Banka S, Newman WG, Ozgül RK, Dursun A. Am J Med Genet A. 2010 Aug 26. PMID: 20799326

- 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

- A syndrome with congenital neutropenia and mutations in G6PC3. Boztug K, Appaswamy G, Ashikov A, Schäffer AA, Salzer U, Diestelhorst J, Germeshausen M, Brandes G, Lee-Gossler J, Noyan F, Gatzke AK, Minkov M, Greil J, Kratz C, Petropoulou T, Pellier I, Bellanné-Chantelot C, Rezaei N, Mönkemöller K, Irani-Hakimeh N, Bakker H, Gerardy-Schahn R, Zeidler C, Grimbacher B, Welte K, Klein C. N Engl J Med. 2009 Jan 1;360(1):32-43. PMID: 19118303

- Impaired neutrophil activity and increased susceptibility to bacterial infection in mice lacking glucose-6-phosphatase-beta. Cheung YY, Kim SY, Yiu WH, Pan CJ, Jun HS, Ruef RA, Lee EJ, Westphal H, Mansfield BC, Chou JY. J Clin Invest. 2007 Mar;117(3):784-93. PMID: 17318259