G6PC3 Deficiency Associated with Congenital Neutropenia and Enterocolitis

Abstract 2170

Glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency causes congenital neutropenia in conjunction with various cardiac or urogenital developmental aberrations.

We here describe a consanguineous pedigree of maroccan descent. Four patients presented with early-onset inflammatory bowel diseases associated with severe congenital neutropenia. Two children died in early childhood, two patients (19-years old female, 17-years old male) are alive with signs of recurrent infections (mouth ulcera, otitis, upper and lower respiratory tract infections) and refractory Crohn's like enterocolitis. Mutations in the Glucose-6-phosphate translocase (SLC37A4) gene were excluded.

In an attempt to discover the underlying molecular pathophysiology, we performed SNP-based homozygosity mapping followed by in depth next-generation exome sequencing. We identified two genes with potentially deleterious homozygous sequence variations: P2RY11 (exon 13; c.C2160G, p.Y720X), encoding a protein with antiapoptotic function, and G6PC3 (exon 2; c.C323T, p.P108L). The G6PC3 mutation segregates with the disease phenotype, whereas the P2RY11 variant was also found in a healthy sibling.

Functional experiments in patient's neutrophil granulocytes showed an accelerated oxidative burst capacity (OxyBurst Assay, Phagoburst Assay). Furthermore, G6PC3-deficient individuals showed a rapid dissipation of the mitochondrial membrane potential upon treatment with valinomycin, whereas the inner mitochondrial membrane potential in neutrophils from healthy individuals was maintained. We observed increased apoptosis in G6PC3-deficient neutrophils upon exposure to staurosporine. Interestingly, increased apoptosis was also seen in granulocytes from the healthy sibling with the P2RY11 sequence variant, suggesting that P2RY11 deficiency may aggravate the phenotype of G6PC3 deficiency.

In summary, our study indicates that the clinical spectrum of G6PC3 deficiency may be more diverse than previously appreciated and that P2RY11 may have a modifying effect on G6PC3-deficient neutrophil granulocytes.

J.D. and D. K. contributed equally to this work and should be considered aequo loco.