A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations

Abstract

The G6PC3 gene encodes the ubiquitously expressed glucose-6-phosphatase enzyme (G-6-Pase β or G-6-Pase 3 or G6PC3). Bi-allelic G6PC3 mutations cause a multi-system autosomal recessive disorder of G6PC3 deficiency (also called severe congenital neutropenia type 4, MIM 612541). To date, at least 57 patients with G6PC3 deficiency have been described in the literature.G6PC3 deficiency is characterized by severe congenital neutropenia, recurrent bacterial infections, intermittent thrombocytopenia in many patients, a prominent superficial venous pattern and a high incidence of congenital cardiac defects and uro-genital anomalies. The phenotypic spectrum of the condition is wide and includes rare manifestations such as maturation arrest of the myeloid lineage, a normocellular bone marrow, myelokathexis, lymphopaenia, thymic hypoplasia, inflammatory bowel disease, primary pulmonary hypertension, endocrine abnormalities, growth retardation, minor facial dysmorphism, skeletal and integument anomalies amongst others. Dursun syndrome is part of this extended spectrum. G6PC3 deficiency can also result in isolated non-syndromic severe neutropenia. G6PC3 mutations in result in reduced enzyme activity, endoplasmic reticulum stress response, increased rates of apoptosis of affected cells and dysfunction of neutrophil activity.In this review we demonstrate that loss of function in missense G6PC3 mutations likely results from decreased enzyme stability. The condition can be diagnosed by sequencing the G6PC3 gene. A number of G6PC3 founder mutations are known in various populations and a possible genotype-phenotype relationship also exists. G6PC3 deficiency should be considered as part of the differential diagnoses in any patient with unexplained congenital neutropenia.Treatment with G-CSF leads to improvement in neutrophil numbers, prevents infections and improves quality of life. Mildly affected patients can be managed with prophylactic antibiotics. Untreated G6PC3 deficiency can be fatal. Echocardiogram, renal and pelvic ultrasound scans should be performed in all cases of suspected or confirmed G6PC3 deficiency. Routine assessment should include biochemical profile, growth profile and monitoring for development of varicose veins or venous ulcers.

Figures

Figure 1

The glucose-6-phosphatase system. A schematic representation of the glucose-6-phosphatase system. Enzymes and genes are displayed in red font, expression sites of the genes are provided within brackets and associated disorders are highlighted in bold.

Figure 2

A flow diagram summarising proposed mechanisms of haematological features of G6PC3 deficiency. G6PC3 deficiency leads to decreased cytoplasmic glucose and glucose-6-phosphate levels [31] and ER stress and activation of protein like ER-kinase (PERK) [9,29]. The lower levels of glucose possibly lead to activation of GSK-3β and phosphorylation of Mcl-1. Activation of these pathways contributes to apoptosis of the cells (this part of the pathway is shown in blue boxes). G6PC3 deficiency also results in aberrant glycosylation of a NADPH oxidase subunit, gp91phox (shown in green box). The precise mechanism of aberrant glycosylation is not clear but may be mediated by perturbation of the Leloir pathway of galactose metabolism (shown in faded green). The final effect of these dysfunctions is maturation arrest of neutrophils, neutropenia and diminished respiratory burst (shown in red boxes).

Figure 3

A summary of G6PC3 mutations. A schematic representation of the G6PC3 gene. The starting and ending nucleotide numbers of the cDNA and their corresponding amino acid residue numbers are provided within each exon. Each mutation is represented once for every family in which it was detected. The inverted triangles represent missense mutations, the block-arrows represent splice-site mutations and stars represent truncating or frame-shift mutations. UTR is untranslated region.

Figure 4

G6PC3 and G6PC alignment and known missense mutations. A ClustalW alignment of G6PC3 and G6PC amino acid sequences. Identical residues are marked by *. Sites where missense mutation has been identified in G6PC3 are highlighted by red arrows. Green arrows highlight missense mutations in GSD1a. The conserved residues are enriched in missense mutations described in two diseases.

Figure 5

G6PC3 multi-species alignment. Multi-species ClustalW alignment of G6PC3. Identical residues are marked by *. Sites where missense mutation has been identified in G6PC3 are highlighted by red arrows. Amino acids in trans-membrane regions are shown under lines of different colours. Note that all the missense mutations affect trans-membrane residues.

Figure 6

Predicted topology of G6PC3 with missense mutations. Residues substituted by missense mutation are highlighted by red circles and the laboratory generated substitutions by blue circles. The S139 residue, predicted in previous publications to be substituted by c.416G > T mutation is highlighted by purple circle. Our analysis suggests that the c.416G > T might be a splice-site mutation (see main text for discussion).