G6PC3 – Autosomal Recessive Severe Congenital Neutropenia Due to G6PC3 Deficiency

Severe congenital neutropenia type 4 (SCN4) is a rare autosomal recessive disorder caused by biallelic mutations in the glucose-6-phosphatase catalytic subunit 3 gene (G6PC3). Clinically, SCN4 presents with profound neutropenia, recurrent bacterial infections, a prominent superficial venous pattern, and variable congenital heart and urogenital anomalies in early childhood. Gastrointestinal manifestations, including inflammatory bowel disease, have emerged as an additional feature in adolescence and adulthood PMID:34964150.

Genetic evidence is robust: over 94 unrelated probands have been described with consistent autosomal recessive inheritance and overlapping syndromic features PMID:34964150. Homozygous or compound heterozygous variants segregate in multiple consanguineous pedigrees, including a four-member kindred PMID:20717171 and two adult siblings with identical mutations PMID:23171239, totaling at least 6 affected relatives.

The variant spectrum encompasses both loss-of-function and missense alleles. More than 20 distinct nonsense, frameshift, and splice-site mutations and over 10 missense changes have been reported, including the recurrent founder allele c.829C>T (p.Gln277Ter) in diverse populations PMID:23758768. This mutation leads to premature termination of the G6PC3 protein and abolishes enzyme activity in vitro.

Functional studies illuminate the pathogenic mechanism: G6PC3 deficiency impairs endoplasmic reticulum glucose recycling, causing neutrophil energy failure, enhanced apoptosis, and defective glycosylation of NADPH oxidase components PMID:21385794, as well as severe defects in neutrophil migration, respiratory burst, and bactericidal activity PMID:33259599.

Murine G6pc3–/– models recapitulate neutropenia via intrinsic mitochondrial apoptosis pathways and disrupted energy homeostasis. Treatment with granulocyte colony-stimulating factor (G-CSF) delays neutrophil apoptosis, restores glucose uptake, normalizes intracellular metabolites, and corrects neutropenia in vivo PMID:21292774. Elevated neutrophil CXCR4 expression contributes to bone marrow retention (myelokathexis) and also responds to G-CSF or CXCR4 antagonism PMID:20616219.

In summary, biallelic G6PC3 mutations definitively cause autosomal recessive severe congenital neutropenia type 4 with a broad multisystem phenotype. Genetic testing for G6PC3 variants is warranted in any unexplained congenital neutropenia. Functional assays and animal models provide concordant evidence for haploinsufficiency, and treatment with G-CSF (and emerging SGLT2 inhibitor strategies) yields clinical benefit. Key take-home: G6PC3 testing enables precise diagnosis and informs targeted therapies in SCN4.

References

• European Journal of Human Genetics • 2011 • Further delineation of the phenotype of severe congenital neutropenia type 4 due to mutations in G6PC3 PMID:20717171
• Orphanet Journal of Rare Diseases • 2013 • A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations PMID:23758768
• Scandinavian Journal of Immunology • 2022 • Severe congenital neutropenia due to G6PC3 deficiency: Case series of five patients and literature review PMID:34964150
• Blood Advances • 2020 • Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects PMID:33259599
• Blood • 2011 • G6PC3 improves murine G6PC3-deficient neutrophil function by modulating apoptosis and energy homeostasis PMID:21292774
• Blood • 2010 • Severe congenital neutropenia resulting from G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexis PMID:20616219

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