Glucose-6-Phosphatase Catalytic Subunit 3 (G6PC3) Deficiency Associated With Autoinflammatory Complications

G6PC3 deficiency typically causes severe congenital neutropenia, associated with susceptibility to infections, cardiac and urogenital abnormalities. However, here we describe two boys of Pakistani origin who were found to have G6PC3 deficiency due to c.130 C>T mutation, but who have clinical phenotypes that are typical for a systemic autoinflammatory syndrome. The index case presented with combination of unexplained fevers, severe mucosal ulcers, abdominal symptoms, and inflammatory arthritis. He eventually fully responded to anti-TNF therapy. In this study, we show that compared with healthy controls, neutrophils and monocytes from patients have reduced glycolytic reserve. Considering that healthy myeloid cells have been shown to switch their metabolic pathways to glycolysis in response to inflammatory cues, we studied what impact this might have on production of the inflammatory cytokines. We have demonstrated that patients’ monocytes, in response to lipopolysaccharide, show significantly increased production of IL-1β and IL-18, which is NLRP3 inflammasome dependent. Furthermore, additional whole blood assays have also shown an enhanced production of IL-6 and TNF from the patients’ cells. These cases provide further proof that autoinflammatory complications are also seen within the spectrum of primary immune deficiencies, and resulting from a wider dysregulation of the immune responses.

[1]  P. Palma,et al.  Inflammatory bowel disease in chronic granulomatous disease: An emerging problem over a twenty years' experience , 2017, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[2]  M. Previati,et al.  Mitochondrial reactive oxygen species and inflammation: Molecular mechanisms, diseases and promising therapies. , 2016, The international journal of biochemistry & cell biology.

[3]  M. McDermott,et al.  Autoinflammatory diseases: update on classification diagnosis and management , 2016, Journal of Clinical Pathology.

[4]  J. Chou,et al.  Functional analysis of mutations in a severe congenital neutropenia syndrome caused by glucose-6-phosphatase-β deficiency. , 2015, Molecular genetics and metabolism.

[5]  F. Martinon,et al.  New players driving inflammation in monogenic autoinflammatory diseases , 2015, Nature Reviews Rheumatology.

[6]  C. Picard,et al.  Clinical spectrum and long-term follow-up of 14 cases with G6PC3 mutations from the French severe congenital neutropenia registry , 2014, Orphanet Journal of Rare Diseases.

[7]  R. Xavier,et al.  IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans , 2014, Proceedings of the National Academy of Sciences.

[8]  C. Weyand,et al.  Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells , 2013, The Journal of experimental medicine.

[9]  W. Newman,et al.  A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations , 2013, Orphanet Journal of Rare Diseases.

[10]  W. Newman,et al.  G6PC3 mutations cause non-syndromic severe congenital neutropenia. , 2013, Molecular genetics and metabolism.

[11]  D. Hardie,et al.  Metabolism of inflammation limited by AMPK and pseudo-starvation , 2013, Nature.

[12]  F. Deist,et al.  Inflammatory Bowel Disease and T cell Lymphopenia in G6PC3 Deficiency , 2012, Journal of Clinical Immunology.

[13]  T. Kuijpers,et al.  Current Concepts of Hyperinflammation in Chronic Granulomatous Disease , 2011, Clinical & developmental immunology.

[14]  J. Orange,et al.  Complications of tumor necrosis factor-α blockade in chronic granulomatous disease-related colitis. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[15]  D. McDermott,et al.  Lack of glucose recycling between endoplasmic reticulum and cytoplasm underlies cellular dysfunction in glucose-6-phosphatase-beta-deficient neutrophils in a congenital neutropenia syndrome. , 2010, Blood.

[16]  Bodo Grimbacher,et al.  A syndrome with congenital neutropenia and mutations in G6PC3. , 2009, The New England journal of medicine.

[17]  M. Novelli,et al.  Inflammatory Bowel Disease in CGD Reproduces the Clinicopathological Features of Crohn's Disease , 2009, The American Journal of Gastroenterology.

[18]  M. McDermott,et al.  The NLR network and the immunological disease continuum of adaptive and innate immune-mediated inflammation against self , 2007, Seminars in Immunopathology.

[19]  D. Greaves,et al.  Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. , 2006, Cell metabolism.

[20]  J. Korzenik,et al.  Association of glycogen storage disease 1b and Crohn disease: results of a North American survey , 2002, European Journal of Pediatrics.

[21]  J. Leonard,et al.  Neutropenia, neutrophil dysfunction, and inflammatory bowel disease in glycogen storage disease type Ib: results of the European Study on Glycogen Storage Disease type I. , 2000, The Journal of pediatrics.

[22]  J. Korzenik,et al.  Is Crohn's disease an immunodeficiency? A hypothesis suggesting possible early events in the pathogenesis of Crohn's disease. , 2000, Digestive diseases and sciences.

[23]  M. Cappell,et al.  Cyclic neutropenia in Crohn's ileocolitis: efficacy of granulocyte colony-stimulating factor. , 1997, Journal of clinical gastroenterology.

[24]  J. Grosset,et al.  Efficacy of granulocyte colony-stimulating factor and RU-40555 in combination with clarithromycin against Mycobacterium avium complex infection in C57BL/6 mice , 1993, Antimicrobial Agents and Chemotherapy.