Glucose-6-phosphatase catalytic subunit 1 (G6PC1) (G6PC1)

Glucose-6-phosphatase catalytic subunit 1 (G6PC1) is a key enzyme anchored in the endoplasmic reticulum membrane, predominantly expressed in the liver, kidney, and intestinal mucosa (UniProt P35575). It plays a pivotal role in glucose homeostasis by catalyzing the hydrolysis of glucose-6-phosphate into free glucose and inorganic phosphate, which represents the terminal step of both gluconeogenesis and glycogenolysis (NCBI Gene: 2538). A deficiency in this enzyme, typically caused by autosomal recessive mutations in the G6PC1 gene, results in Glycogen Storage Disease Type Ia (GSD Ia), also known as Von Gierke disease (StatPearls: NBK448176). This metabolic disorder leads to the inability to maintain blood glucose levels during fasting, resulting in severe hypoglycemia, hepatomegaly, and the accumulation of glycogen and lipids in the liver (PubMed: 30054005). Current therapeutic strategies are shifting from lifelong dietary management with uncooked cornstarch toward advanced genetic medicines, such as adeno-associated virus (AAV) gene therapies like DTX401 and mRNA-based treatments like UX053, which aim to restore endogenous G6PC1 activity (Ultragenyx Pharmaceutical Inc.; ClinicalTrials.gov: NCT03517085).

Other names

G6PaseGlucose-6-phosphatase alphaG6PCVon Gierke disease antigenGSD1a

Restoration of G6PC1 enzyme activity through AAV-mediated gene replacement or mRNA-mediated protein expression to facilitate hepatic glucose production (Ultragenyx; PubMed: 30054005).