G6PC1 (glucose-6-phosphatase catalytic subunit 1; HGNC:4056, NCBI Gene ID 2538) is a human locus mapped to chromosome band 17q21.31 that encodes endoplasmic reticulum 9-transmembrane glucose-6-phosphatase catalytic subunit (357 aa; EC 3.1.3.9). G6PC1 acts in terminal step of hepatic & renal glycogenolysis and gluconeogenesis, together with GCK (Glucokinase Gene), GYS2 (Hepatic Glycogen Synthase 2 Gene), and FOXO1 Transcription Factor Gene. Encodes the endoplasmic reticulum glucose-6-phosphatase catalytic subunit required for hepatic glucose release during fasting.
Terminal step of hepatic & renal glycogenolysis and gluconeogenesis
Clinical / Therapeutic Role
Biallelic LoF causes Glycogen Storage Disease Type Ia (von Gierke disease); target of AAV8 gene therapy & mRNA therapy
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 5-exon gene on chromosome 17q21.31 (officially designated G6PC1, historically G6PC) whose promoter contains insulin-repressible FOXO1/HNF4alpha/PGC-1alpha response elements and glucocorticoid- and cAMP/CREB1-inducible elements.
Cellular & Tissue Expression Profile: Expressed strictly in the endoplasmic reticulum membrane of hepatic hepatocytes, renal proximal convoluted tubule epithelial cells, and small intestinal mucosa—the only three human tissues capable of releasing free glucose into the bloodstream.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Coupled functionally with the glucose-6-phosphate translocase (SLC37A4 / G6PT1), G6PC1 exposes its His176 nucleophilic catalytic site inside the endoplasmic reticulum lumen to hydrolyze glucose-6-phosphate into free D-glucose and inorganic phosphate as the compulsory final step of both glycogenolysis and gluconeogenesis.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Biallelic loss-of-function mutations (such as p.Arg83Cys and p.Gln347Ter) cause autosomal recessive Glycogen Storage Disease Type Ia (von Gierke disease), presenting in infancy with life-threatening fasting hypoglycemia, severe lactic acidosis, hyperuricemia (from shunting of G6P into the pentose phosphate pathway), hypertriglyceridemia, massive hepatomegaly, and hepatic adenomas.
Therapeutic & Clinical Pharmacology: Clinical candidate for intravenous AAV8-mediated gene replacement therapy (pariglasgene brecaparvovec / DTX401), lipid-nanoparticle mRNA replacement, and CRISPR prime/base editing of the recurrent p.Arg83Cys variant.